Spine Healing Therapy

Dorn Spinal Therapy

Dorn Spinal Therapy has been in uses in the past 40 years. The credit of this method goes to Dieter Dorn, who has made a significant impact in the medical field. DORN- Method has been used on various patients where results could get witnessed instants. Due to the impact, this method has brought in the country. It has been declared the standard practice in treating Pelvical Disorders, Spinal, and Back pain. Dieter Dorn first used this method on his family, which was a sign of confidence in a method, which later gained much attention from different people in the country and also globally. Every day Dorn was able to offer treatment to 15- 20 patients in a day. His services were purely free which attracted attention both in the local and also global. The primary treatment that DORN-Method which could be treated using this method include spine healing therapy, misalignments of the spine, resolving pelvis and joints, and also solving out significant problems which could get attributed to vertebrae. Continue reading...

Dorn Spinal Therapy Summary

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Intrathecal spinal anesthesia

Early ambulation has previously been implicated in transient radicular irritation. However, in a randomized trial there was no difference between early and late mobilization in patients who received spinal lidocaine 2 for inguinal hernia repair the incidence was 23 in both groups (15C). Procaine has been suggested as an alternative to lidocaine for spinal use in ambulatory surgery, as it also has a short duration of action. In a randomized, double-blind comparison of procaine 10 or lidocaine 5 in glucose 7.5 for spinal anesthesia transient radicular irritation occurred in 27 of the lidocaine group compared with none of the patients in the pro-caine group (16C). However, the failure rate in the procaine group was 14 . This was perhaps a reflection of the fact that the procaine was glucose-free, but further studies are required with procaine to evaluate its use in this context. Intrathecal hyperbaric lidocaine 1.5 has been compared with hyperbaric bupivacaine 0.75 for outpatient...

Epidural and spinal analgesiaanesthesia in pregnancy

These methods (epidural anesthesia, spinal anesthesia, or a combination of both methods) are commonly used for pain relief during labor or for cesarean deliveries because they are immediately effective, the failure and complication rates are low, ambulation is possible, and they do not seem to interfere with the progress of labor (Mattingly 2003, Albright 2000). Among the many anesthetics used are lido-caine, bupivacaine, ropivacaine, and fentanyl. These agents have already been discussed individually (see above). Most studies looking at the effects of this type of anesthesia on the newborn infant showed some slight and transitory effects, with clearing of symptoms and elimination of the drugs from the infant's circulation within 24 hours. There seem to be no studies on the possible long-term effects of cpidural spinal analgesia on the development of the children.

Distribution of CB1R mRNA and CB1R Immunoreactivity in Spinal Cord

The presence of CB1R mRNA in rat dorsal horn has been reported (Mailleux and Vanderhaeghen 1992). Hohmann (2002) characterized the laminar distribution of CB1R mRNA-expressing cells in rat lumbar spinal cord using a highly sensitive cRNA probe. CB1R mRNA was found in all spinal laminae except lamina IX motoneurons in this region, which are immunoreactive for fatty acid amide hydrolase (FAAH) (Tsou et al. 1998b), were CB1R mRNA negative. Expression was dense in lamina X and sparsest in III and IV. CB1R mRNA was highly expressed in lamina V and VI and the medial part of IV. These laminae contained many large cells with high levels of expression. In general, primary afferents that project to deeper parts of the dorsal horn (here III-VI) include coarser caliber fibers than those projecting to the superficial laminae, although small diameter fibers are also observed. Small-diameter fibers from viscera also project to lamina V, VII, and X (see Grant 1995 for review). By contrast, the...

Evidence for CB1Rs on Spinal Interneurons

There is considerable support for localization of CBRs in rat spinal cord postsynaptic to primary afferents at both light and electron microscope levels. Direct evidence for postsynaptic localization of CB1 in spinal dorsal horn is derived from the observation that intrinsic excitatory interneurons in lamina IIi that expressed protein kinase C isoform y showed high levels of colocalization with CB1 (Farquhar-Smith et al. 2000) this pattern may suggest an anatomical basis for the efficacy of cannabinoids in ameliorating inflammatory and neuropathic pain (Bridges et al. 2001 Fox et al. 2001 Herzberg et al. 1997 Malmberg et al. 1997 Mao et al. 2000). CB1R immunoreactivity has also been localized to dorsal horn interneurons containing y-aminobutyric acid (GABA) (Salio et al. 2002b). GABA presynaptically inhibits primary afferent input to the spinal cord. The observation of GABAergic dendrites postsynaptic to primary afferents also suggests that primary afferents are anatomically...

Evidence for CBIRs on Afferents Originating Supraspinally

CB1R immunoreactivity is highly expressed at all spinal levels in fibers of the dorsolateral funiculus (DLF) and in the intermediolateral nucleus (Farquhar-Smith et al. 2000). Interruption of descending pathways (and ascending pathways from lamina I) that course in the DLF produced only a 5 change in CB1R immunoreactivity (Farquhar-Smith et al. 2000). These data suggest that CB1R immunoreactivity, in general, is not localized on terminals of neurons originating supraspinally and suggest localization of CB1R to intrinsic spinal neurons and or ascending projections (Farquhar-Smith et al. 2000). Because visceral primary afferents project to the nucleus of the DLF, CB1Rs are appropriately positioned to influence visceral afferent input as well as viscero-somatic integration (Farquhar-Smith et al. 2000). These observations are consistent with cannabinoid modulation of visceral hyperalgesia (see Hohmann 2002 for review). Ascending projections to the brainstem, hypothalamus, and thalamus...

Antinociceptive and Electrophysiological Effects of Spinally Administered Cannabinoids

Antinociceptive effects of cannabinoids are mediated, in part, at the spinal level. Spinal reflexive responses to noxious stimuli are inhibited by cannabinoids in spinally transected dogs (Gilbert 1981). Support for spinal mechanisms of cannabinoid analgesic action is also derived from the ability of intrathecally administered cannabinoids to produce antinociception (Smith and Martin 1992 Welch et al. 1995 Yaksh 1981). The behavioral data are consistent with the ability of spinally administered cannabinoids to suppress noxious heat-evoked and after-discharge firing (Hohmann et al. 1998) and noxious stimulus-evoked Fos protein expression in the spinal dorsal horn neurons (Hohmann et al. 1999c). Spinal administration of a CB1R-selective agonist also inhibits C fiber and A6 fiber-evoked responses of wide dynamic range (WDR) neurons through a CB1R mechanism with only minor effects on A-3 fiber-evoked responses (Kelly and Chapman 2001). Systemic and intrathecally administered cannabinoids...

Antinociception Mediated by CB1Rs in Supraspinal Pain Circuits

Support for supraspinal sites of cannabinoid antinociceptive action is derived from the antinociceptive effects of cannabinoids following intracerebroventricu-lar administration (Hohmann et al. 1999b Martin et al. 1993) and the attenuation of cannabinoid antinociception following disruption of communication between brain and spinal cord. Both the antinociceptive (Lichtman and Martin 1991b) and electrophysiological (Hohmann et al. 1999b) effects of systemically administered cannabinoids are attenuated following spinal transection, suggesting the involvement of supraspinal sites of cannabinoid analgesic action. Intrathecal administration of the a2 antagonist yohimbine but not the serotonin antagonist methysergide also blocks the antinociceptive effect of systemically administered A9-tetrahydrocannabinol (A9-THC) (Lichtman and Martin 1991a). Furthermore, the antinociceptive efficacy of systemically administered cannabinoids is markedly attenuated following neurotoxic destruction of...

Suppression of noxious stimulusevoked expression of cfos in spinal cord by cannabinoids

Hunt et al. (1987) demonstrated that noxious stimuli induce the expression of the immediate early gene c-fos in the spinal dorsal horn, and this response is diminished by analgesics such as morphine (Presley et al., 1990). This laboratory first studied the effects of cannabinoids on the neural processing of pain by examining their effects on spinal c-fos expression induced by injections of dilute formalin in the hindpaw (Tsou et al., 1995). The cannabinoid agonist WIN 55,212-2 markedly suppressed this effect. The mediation of the actions of WIN 55,212-2 by canna-binoid receptors was indicated by the dose-dependency of the effect, its reduced magnitude in cannabinoid-tolerant animals, and the lack of efficacy of the canna-binoid receptor-inactive enantiomer WIN 55,212-3.

Cannabinoid suppression of responses to noxious stimuli in spinal wide dynamic range and nociceptive specific neurons

The suppression of pain-induced expression of an immediate early gene by a cannabinoid agonist suggested that cannabinoids suppress the spinal processing of nociceptive messages, but many questions remained that were better addressed using neurophysiological methods. One of these was, whether can-nabinoids suppress noxious stimulus-evoked firing of wide dynamic range and nociceptive specific neurons. These studies were carried out in urethane-anesthetized rats using the cannabinoid agonists WIN 55,212-2 and CP 55,940. Three types of noxious stimuli were used noxious pressure applied to regions of the ipsilateral hind paw corresponding to the receptive field of the recorded neuron (Hohmann et al., 1995), noxious thermal stimuli applied by a Peltier thermode (Hohmann et al., 1998 Hohmann and Walker, 1999), or painful C-fiber strength electrical stimulation (Strangman and Walker, 1999). Low doses (62.5 Mg kg to 500 g kg, i.v.) of the cannabinoid agonists produced a profound inhibition of...

Supraspinal controls 5Hydroxytryptamine Antidepressants

Spinal Inhibitory Neurons Following the description and then isolation of opioid receptors, there were three known receptors for the opioids, the mu, delta and kappa opioid receptors, but a novel fourth receptor, the orphan receptor, has been characterised very recently. This newly discovered opioid receptor-like (ORL-1) receptor appears to be linked to an inhibitory receptor despite the endogenous agonist having been named nociceptin (orphanin FQ). The receptor system does not appear to be anything like the traditional opioids. Overall, this peptide produces spinal analgesia but may well function as an 'anti-opioid' at supraspinal sites and cause excitation of C-fibres in the periphery. The central effects of nociceptin include a low abuse potential compared to morphine, and so provide an opportunity for the development of alternative analgesics to morphine. However, sufficiently selective tools for the receptor are lacking the peptide itself is the only agonist available at present,...

Spinal Opiate Analgesia

Opioids act in the brain and within the dorsal horn of the spinal cord, where their actions are better understood. The actions of opioids important for analgesia and their side-effects involve pre- and postsynaptic effects (1) reduced transmitter release from nerve terminals so that neurons are less excited by excitatory transmitters, and (2) direct inhibitions of neuronal firing so that the information flow from the neuron is reduced but also inhibitions of inhibitory neurons leading to disinhibition. This dual action of opioids can result in a total block of sensory inputs as they arrive in the spinal cord (Fig. 21.5). Thus any new drug would have to equal this dual action in controlling both transmitter release and neuronal firing. C-fibre stimulation will release a number of transmitters in the spinal cord including substance P, CGRP, glutamate and aspartate. By actions on their receptors the peptides produce slow depolarising responses of dorsal horn neurons which in concert with...

Symptomatic Relief in Multiple Sclerosis and Spinal Cord Injury

Spasticity is a central feature of multiple sclerosis (MS) and spinal cord injury (SCI). It consists of a velocity-dependent increase in tonic stretch reflexes with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex as one component of the upper motor syndrome (Young 1994). Existing drug therapy is far from satisfactory in terms of efficacy and unwanted effects (Panegyres 1992). Tremor, ataxia and lower urinary tract symptoms are frequently troublesome in MS. Both neuropathic and nociceptive pain (dealt with in Sect. 2.3) are also common in MS and SCI, and dozens of very painful muscle spasms can occur each day. Small wonder that there is also a high incidence of anxiety and depression in these conditions. mented that the primary outcome measure does not correlate with function or other measures of spasticity. It recommended that future studies should consider the potential confounding effect of including patients with severe spinal cord disease and...

Spinal cord and dorsal root ganglion

Numerous fibers labeled for CBX receptors are found in the spinal cord and are especially numerous in the dorsal horn. At least half of the binding in the dorsal horn has a presynaptic origin on dorsal root ganglion input terminals. Fibers extending from the white matter into the grey matter are observed under the central canal. Cells with a very light sheet of immunoreactivity are observed throughout the grey matter of the spinal cord. Very lightly labeled neurons and their processes are observed in the ventral horn. The amount of immunoreactivity for CBj cannabinoid receptors is much higher in the dorsal root ganglion than in the spinal cord. Many neurochemically different cells in the dorsal root ganglion express the receptor with varying intensities. Also, both dorsal and ventral roots show labeled fibers as does the peripheral nerve which agrees with the reported axonal flow of CBX cannabinoid receptors in peripheral nerves (Glass et al., 1997 Herkenham et al., 1991c Hohmann and...

Intraspinal injection

Glucocorticoids given intrathecally can cause a rise in cerebrospinal fluid protein and carry the risk of arachnoiditis (SED-8, 820). Chemical meningitis has been reported after two intrathecal injections of methylpredni-solone acetate (384) and after lumbar facet joint block (SEDA-17, 450). Intraspinal injections of hydrocortisone for multiple sclerosis apparently led in one case to a cauda equina syndrome, with subsequent ulceromutilating acropathy (SEDA-17, 450). Intra-discal injections of triamcinolone acetonide in a number of French cases led to disk or epidural calcification, sometimes symp-tomless (SEDA-17, 450). Spinal epidural lipomatosis secondary to exogenous administration of glucocorticoids is a rare condition that has been reported almost exclusively in association with systemic treatment. However, local epidural administration has also been implicated (389).

Supraspinal Opiate Analgesia

Opiate receptors in these zones (mu, delta and kappa) when activated alter the level of activity in descending pathways from these zones to the spinal cord. The mechanisms of action of opioids at supraspinal levels are still poorly understood. One idea is that descending controls filter sensory messages at the spinal level allowing a pain message to be extracted from the incoming barrage. Supraspinal morphine is thought to reduce these controls so blurring the perception of pain. The second theory is that morphine turns on descending controls which simply inhibit spinal pain transmission. The relative roles of the 5-HT receptors in the spinal cord are yet unknown but the spinal target for the noradrenaline released from descending pathways is alpha-2 receptors which have similar actions and distribution to the opiate receptors. Sedation and hypotension with alpha-2 agonists presently limit their use as analgesics.

Spinal Cord

Because of the efficacy of intrathecal cannabinoids in various pain models, it is not surprising that moderate levels of CB1 receptor are found in the regions of the spinal cord associated with analgesia. In particular, the superficial layers of the dorsal horn, the dorsolateral funiculus, and lamina X all have moderate levels of CB1 receptor (Farquhar-Smith et al. 2000). Cannabinoids inhibit glutamate release from afferents in lamina I of the dorsal horn in a CB1 receptor-dependent fashion (Jennings et al. 2001 Morisset and Urban 2001). Providing anatomical support for these functional studies, CB1 receptors are found in the dorsal horn in a characteristic twin band corresponding to lamina I and the inner portion of lamina II (Farquhar-Smith et al. 2000). The source of CB1 receptors in the dorsal horn remains controversial. One im-munocytochemical study found little decrease in CB1 receptor immunoreactivity following dorsal rhizotomy or hemisection of the spinal cord, suggesting CB1...

Spinal Problems

Five other patients with a variety of spinal problems have benefited from using nabilone but have had to stop either because of side effects or because of difficulties in assessment. Two patients found nabilone completely ineffective to manage the pain. Both of them had had multiple spinal operations and suffered both mechanical spinal pain and neurogenic pain from nerve scarring.

Organs and Systems Cardiovascular

Cardiovascular reactions to acrylic bone cement are a common complication in bone surgery. It is believed that cementation activates an adrenocortical response, increasing the blood pressure during general anesthesia (6,7) during spinal anesthesia this response is suppressed and the blood pressure falls. The mechanism is thought to be by a direct effect on the blood pressure through the kallikrein-kinin system, since aprotinin (Trasylol), an inhibitor of kallikrein, prevents the fall in arterial pressure if it is given during the application of acrylic bone cement (8).

Needles and a glass syringe for punctures The upper big needle is used for stomach puncture the smaller one for cardiac

According to the need, cerebrospinal fluid (CSF), hair and nails are sampled. CSF is sampled by suboccipital puncture as follows. The neck is bent forward, and the needle is stuck from the backside at the level between the foramen magnum and the first jugular vertebra to reach the cisterna magna more than 10 mL of CSF can be obtained by such puncture. As stated before, there are many cases in which basic drugs or poisons are relatively stably retained in hair or nails for a long time hair and nails sometimes become good alternative specimens for analysis of drugs and poisons in putrefied cadavers, and may be also useful for detection of toxins which had been taken or administered in the past. The utility of hair and nails is presented in Chapter I.2 entitled Alternative specimens of this book.

Cannabinoid Receptor Mediated Regulation of Ion Channels

Studies of the effects of cannabinoid drugs on neurophysiological responses in the years prior to the elucidation of the existence of a cannabinoid receptor were targeted at investigating a mechanism for the anticonvulsant properties of cannabidiol and mixed excitatory properties of A9-THC (for a description and other original references see Karler and Turkanis 1981 Turkanis and Karler 1981). The laboratory of Karler and Turkanis used an in vivo model of cat spinal motor neurons to observe changes in amplitude of excitatory post-synaptic potentials evoked by these cannabinoid compounds (Turkanis and Karler 1983,1986). These researchers also used cultured neuroblastoma cells to identify A9-THC and 11-OH-A9-THC-induced depression of inward Na+ currents, suggesting a possible mechanism for CNS depression by these compounds (Turkanis et al. 1991).

Results in the NAc and Striatum

Bhargava and Kumar (51) treated mice with a sensitizing regimen of cocaine (10 mg kg, twice daily for 7 d). Immediately after drug treatment, 3H MK-801 binding was increased in cerebellum and spinal cord but decreased in cortex and hypothalamus. After withdrawal, binding remained decreased in cortex but other changes normalized.

Cannabinoid Receptor Mediated Nitric Oxide Production

NO and peroxynitrite in human endothelial cells, human embryonic kidney (HEK) cells, and C6 glioma cells promoted activation of the anandamide and 2-AG transporter(s) (Maccarrone et al. 2000 Bisogno et al. 2001 De Petrocellis et al. 2001). This phenomenon may have ramifications for cellular mechanisms that require anandamide as a regulator. For example, indomethacin is thought to augment anandamide's stimulation of CB1 receptors in a model of inflammatory hyperalgesia by reducing spinal NO and relieving the activation of the anandamide transporter (Guhring et al. 2002). The net result would be increased extracellular concentrations of anandamide with decreased concentrations of NO, producing an antinociceptive response that was not reversed by prostaglandin E2 (Guhring et al. 2002). Another example is the potential for NO to activate the anandamide transporter leading to increased intracellular accumulation of anandamide where

Phosphorylation of the Cannabinoid Receptors as a Mechanism for Desensitization

The role of protein kinases in maintaining the tolerant state in rodents was examined by the Welch laboratory (Lee et al. 2003). In those studies, animals were chronically exposed to 49-THC, and then tested for their antinociceptive response to a dose of 49-THC. The tolerance to 49-THC was reversed by prior administration of a PKA inhibitor and a Src family tyrosine kinase inhibitor. These studies suggested that PKA and a tyrosine kinase could be important in maintaining the tolerant state. It is intriguing to speculate on what these findings might imply regarding the signal transduction pathways that might include cannabi-noid receptors. However, the complexity of the intact brain and spinal cord in the nociceptive response makes it difficult to assign any particular substrate for PKA, or Src tyrosine kinases, as the target(s) for these phosphorylation-dependent changes.

General adverse effects

Of antinicotinic and antimuscarinic activity of atropine itself. Of the synthetic compounds used in visceral disorders, the quaternary compounds are fully ionized in the pH range found in body fluids and are therefore less lipid-soluble than the corresponding tertiary amines. This means that they penetrate physiological barriers less readily less drug is absorbed in the intestine, less enters the cerebrospinal fluid and aqueous humor, and less enters cells. Consequently, these drugs tend to be relatively less active by mouth and to have fewer effects on the brain and the eye than the tertiary amines. Of the latter, some have little antimuscarinic activity and indeed probably very little useful activity at all they may have some specific relaxant effect on smooth muscle, but it seems to be of little clinical significance.

Human clinical studies

Recently, Mikuriya (1999) reported on interviews of 1800 patients who used marijuana for various medical conditions. Of these patients, he reported that 41 experienced analgesia following traumatic inflammation induced pain, autoimmune disorder-induced pain and ideopathic pain. Similarly, Consroe et al. (1997) found self-reported reductions in pain in patients with multiple sclerosis. Consroe et al. (1998) found similar self-reported pain reduction in patients with spinal cord injury. Schnelle et al. (1999) used an anonymous standardized survey of the medical use of cannabis and cannabis products of patients in Germany, Austria and Switzerland. Data from 128 170 patients were usable. Of these, 5.4 used cannabis for back pain and 3.6 for headache. Table 2.2 lists human studies of cannabinoid effects on pain.

Neuroprotective Effect of Naloxone Stereoisomers on Dopaminergic Neurons in the Inflammation Related Model of PD

The establishment of both in vitro and in vivo inflammation-related models of PD has enabled the search for and study of the mechanism of action responsible for a variety of neuroprotective agents. Of particular interest is the neuroprotective effect of the naloxone stereoisomers. In the in vitro neuron-glia culture system, 1 M (-)-naloxone afforded significant protection of dopaminergic neurons against LPS-induced degeneration. Interestingly, (+)-naloxone, which lacks opioid receptor binding activity, was equally effective (69). The neuroprotective effect of naloxone was most likely unrelated to the opioid system because both compounds effectively inhibited the activation of microglia and their production of NO, TNF-a, and especially the superoxide free radical (69,82 Fig. 2). The in vitro observations were confirmed by in vivo studies where systemic administration of naloxone with an osmotic minipump reduced the loss of nigral dopaminergic neurons induced by LPS injection (67,68)....

Family Fumariaceae A P de Candolle 1821 nom conserv the Fumitory Family

Isoquinoline alkaloids Corydalis, Dicentra and Fumaria species are toxic on account of isoquinoline alkaloids such as bulbocapnine, protopine, and bicu-culline. Bulbocapnine is a dopaminergic antagonist which has been used as a sedative in postencephalitic conditions, Meniere's syndrome, and for tremors of various origins (dose 100 mg, orally or subcutaneously, once or twice daily). Protopine, is the principal alkaloid of jaundice herb or Fumaria officinalis L. (Common fumitory,French Pharmacopoeia, 10th edition) which has been used to treat liver disorders and to invigorate. This protoberberine is spasmolytic, anticholinergic, antiarrhytmic, antibacterial and increases the binding of y-aminobutyric acid to its central receptor. Bicuculline, like picrotoxin, is a specific GABA receptor blocking agent which impedes the GABAergic presynaptic inhibition of excitatory transmission of primary afferent neurones of the spinal cord resulting in epileptiform convulsions, myosis, and dyspnea...

Drug administration route

Drugs injected directly into the cerebrospinal fluid have a tendency to produce unpredictable effects, their spread being influenced not only by the volume administered, but also by the concentration of the drug, its specific gravity in relation to that of cerebrospinal fluid, the positioning of the patient (head-up or head-down), and on the speed of injection of bolus doses. Truncal muscle spasms can also increase the spread of drug within the cerebrospinal fluid. All these parameters need to be taken into consideration. Standardization is required as a first step. Rapid bolus injection in particular can produce unexpectedly severe adverse effects.

Participation of the CB1 Cannabinoid Receptors in the Control of Pain

Cannabinoids produce antinociception through multiple mechanisms at peripheral, spinal and supraspinal levels through CB1 and CB2 cannabinoid receptors in several animal species, including mice, rats, rabbits, cats, dogs, monkeys and humans (Pertwee 2001). These responses were revealed in multiple acute nociceptive models using thermal (Buxbaum 1972 Hutcheson et al. 1998 Martin and Licht-man 1998), mechanical (Smith et al. 1998), chemical (Bicher and Mechoulam 1968 Welch et al. 1995) and electrical stimuli (Bicher and Mechoulam 1968 Weissman et al. 1982). Cannabinoid agonists also induce antinociception in inflammatory models of pain, including hyperalgesia induced by carrageenan (Mazzari et al. 1996), capsaicin (Li et al. 1999), formalin (Calignano et al. 1998 Jaggar et al. 1998) or Freund's adjuvant (Martin et al. 1999). Cannabinoid agonists are also effective in visceral models of pain, such as inflammation of the bladder wall induced by turpentine administration (Jaggar et al....

Description And Effects

The short-term effects of crack are similar to those of cocaine and include euphoria, stimulation of the central nervous system (the brain and the spinal cord), reduced fatigue, and a sense of mental clarity. Because crack is smoked, it is absorbed more quickly into the body and produces a more intense reaction than snorting powder cocaine. However, the faster the drug is absorbed, the shorter the duration of its effect. The short-term effects of crack typically last only about 5-10 minutes. Frequent use of crack can lead to tolerance of the drug, a condition in which the user must increase his or her intake of the drug to achieve the same effects. At higher doses crack use can lead to paranoia and trigger aggressive behavior. Long-term effects include restlessness, irritability, and anxiety.

Biosynthesis of 2Arachidonoylglycerol

Although probably over-estimated due to artefactual production, for example following rat decapitation (Sugiura et al. 2001), the levels of 2-AG in unstimulated tissues and cells, but not in the blood or cerebrospinal fluid (CSF), are usually much higher than those of AEA, and sufficient in principle to permanently activate both cannabinoid receptor subtypes (Sugiura et al. 1995 Stella et al. 1997). This simple observation, and the fact that this compound is at the crossroads of several metabolic pathways and is an important precursor and or degradation product of phospho-, di- and triglycerides, as well as of arachidonic acid, indicates that the 2-AG found in tissues is not uniquely used to stimulate cannabinoid receptors, although the one measured in extracellular fluids, such as serum and CSF, probably is. While an enhancement of intracellular Ca2+ is necessary and sufficient for AEA biosynthesis, 2-AG formation is triggered also, but not only, by Ca2+-mobilizing stimuli (and,...

Using Epidural Pain Management

Administration of certain narcotic analgesics, specifically morphine and fentanyl, by the epidural route has provided an alternative to the intramuscular or oral route. Epidural administration is performed when a catheter is placed into the epidural space, which is the space outside of the dura matter of the brain and spinal cord. The analgesic effect is produced by the direct effect on the opiate receptors in the dorsal horn of the spinal cord. This approach was introduced with the idea that very small doses of narcotic would provide long-lasting pain relief with systemic adverse reactions. Epidural administration offers several advantages over other routes. Lower total dosages of the drug used, fewer adverse reactions, and greater patient comfort are all benefits seen with epidural administration. Spinal cord Epidural space Spinal cord Epidural space between the dura mater and the vertebral column (Fig. 19-2). Drug injected through the catheter spreads freely throughout all the...

Transcription Factor Pet1

While the transcription factors Nkx2.2 and Gli2 are also required for induction of floor plate and adjacent cells including both serotonergic and dopaminergic neurons throughout the midbrain, hindbrain, and spinal cord (van Doorninck et al. 1999), expression of Pet1 is restricted to the rostrocaudal extent of hindbrain raphe nuclei and closely associated with developing seroton-ergic neurons in the raphe nuclei (Hendricks et al. 1999 Pfaar et al. 2002) (Fig. 1). Pet1 is therefore likely to be distinct from other factors because its expression pattern suggests that it performs a strictly serotonergic-specific function in the brain. Moreover, consensus Pet1 binding motifs are present in

Brain Receptors And Natural Opiates

Opiate molecules produce their effects on the human body by binding to receptors on specific neurons of the central nervous system. The central nervous system (the brain and spinal cord) controls all functions in the body. It is a complex structure that has two main types of cells structural support cells, or glia, and neurons, which are cells that receive and transmit information. The main areas of the brain that are affected by opiate drugs are the cerebral cortex, the limbic system, the thalamus, the hypothalamus, and the brain stem. Four types of opioid receptors have been identified in the central nervous system mu (p.), kappa (k), delta (8), and sigma (a). Heroin (morphine) effects are mediated mainly by its interaction with mu and kappa receptors. Both receptors are involved with analgesia. Mu receptors are especially abundant in the limbic system, thalamus, hypothalamus, and brain stem kappa receptors are abundant in the cerebral cortex and spinal cord. constipation associated...

Reacting To Pain Without Thinking

Even though all pain signals are transmitted to the brain, not all of our responses to pain are carefully thought out. Some responses occur right in the spinal cord, bypassing the brain's input completely. The human body has developed this remarkable ability to react to pain without even thinking, probably because certain types of injuries require such an immediate response that waiting for pain signals to be processed and interpreted by the cerebral cortex would result in too much tissue damage before the appropriate response command could be given. Figure 1.3 This diagram illustrates the pain withdrawal reflex. Note how, once the nerve fibers get inside the spinal cord, they split into one branch that goes up to the brain and another branch that goes to the leg muscles to initiate a response before the signals even reach the brain. Figure 1.3 This diagram illustrates the pain withdrawal reflex. Note how, once the nerve fibers get inside the spinal cord, they split into one branch...

Introduction Understanding Endocrine Behavior Interactions Lessons from Mutant Mice

Anxiety disorders are common, and lifetime prevalence for the group of disorders is estimated to be as high as 25 (Kessler et al. 1994). These disorders display a substantial lifetime and episode comorbidity between each other and between other psychiatric conditions, particularly mood disorders (Hettema et al. 2001). With respect to the neuroendocrine phenotype, increased concentrations of corticotropin-releasing hormone (CRH) in the cerebrospinal fluid have been reported in stress-related clinical conditions (Holsboer 1999, 2003). In major depression, the combined dexamethasone (DEX) CRH test, in which DEX-pretreated subjects receive a single dose of CRH, has proved to be the most sensitive tool for the detection of altered hypothalamic-pituitary-adrenocortical (HPA) regulation. Depending on age and gender, up to 90 of patients with depression show this neuroendocrine phenomenon (Heuser et al. 1994). Panic disorder patients do not show any relevant alterations in their basal...

Organs and Systems Nervous system

Cauda equina syndrome has been reported after a spinal anesthetic using cinchocaine (2). A 64-year-old man with a history of borderline diabetes who had undergone two previous operations uneventfully under spinal anesthetic received a spinal anesthetic with hyperbaric 0.24 dibucaine 2.2 ml and then a general anesthetic because of unilateral block. The next day he complained of difficulty in defecation and urination, with abnormal anal sensation. A diagnosis of cauda equina syndrome was made. He made a gradual recovery, but mild hypesthesia remained after 4 months. A possible cause for this adverse event may have been maldistribution in the intrathecal space of the high concentration of cinchocaine, affecting the cauda equina and resulting in nerve damage the incomplete block achieved in this case is suggestive of this. Elderly patients undergoing urological surgery often have risk factors for cauda equina syndrome, such as intraoperative lithotomy position, frequent spinal...

Discovery of endogenous dlis

Present after discontinuation of digoxin therapy (5). Balzan et al. (6) also confirmed the presence of DLIS in human plasma and urine. DLIS were found in various human body fluids and tissues including cord blood, placenta, amniotic fluid, bile meconium, cerebrospinal fluid, and saliva (7,8). DLIS cross-react with anti-digoxin antibodies as well as inhibit Na, K-ATPase.

DLIS Concentrations and Therapeutic Range of Digoxin

Lusic et al. reported comparable plasma and cerebrospinal fluid levels (CSF) of DLIS in 40 patients diagnosed with aneurysmal subarachnoid hemorrhage. On the first day, DLIS concentrations were detected in sera of 34 patients (range 0-0.86 ng mL,) and CSF of 32 patients (range 0-1.01 ng mL). On the seventh day post hemorrhage, DLIS were present in plasma of 37 patients (range 0-1.52 ng mL) and in CSF of 38 patients (range 0-1.67 ng mL). The authors used an FPIA (Digoxin II, Abbott Laboratories) for their study (35).

Other Endocannabinoids and AEA Congeners and VR1 Receptors

Recently, a synthetic AEA analog, NADA, previously shown to activate 03, receptors as efficaciously as AEA (Bisogno et al., 2000), was identified in bovine and rat nervous tissues, with the highest levels found in the striatum and hippocampus, and relatively low levels in sensory neurons. Most important, NADA was shown to potently activate both human and rat recombinant VR1 (Huang etal., 2002). By acting on native rat VR1 receptors, NADA was also more potent than AEA at inducing CGRP and substance P release from spinal cord slices, and at causing intracellular calcium rises in dorsal root ganglion neurons, and was almost as active as capsaicin at enhancing paired-pulse inhibition in the rat hippocampus. A possible NADA metabolic product, O-methyl-NADA, was much less active as a VR1 agonist (Huang etal., 2002) and did not affect paired-pulse inhibition (Al-Hayani etal., 2003), thus suggesting that methylation by catechol O-methyl transferase might be a way to terminate the effect of...

Poliomyelitis vaccine

Based on the observation of more than 15 000 pregnancies, there was no increased risk of spontaneous abortion and no increase in birth defects or prematurity (Harjulehto-Mervaala 1995, Ornoy 2006, 1993, 1990). The authors consider the oral poliovirus vaccine as safe for pregnant women however, it should not be used in the last month of pregnancy, to avoid contamination of delivery rooms by the virus-shedding mother. Live attenuated poliovirus is no longer relevant as a result of practical extinction of the disease, at least in the developed world. Polio-like changes (damage to the anterior horn cells of the spinal cord) were noted in a fetus aborted at 21 weeks' gestation when the previously immune mother received oral polio vaccine at 18 weeks (Castlcman 1964), but no similar effect has been published since.

Preparing the Patient for Local Anesthesia

Depending on the procedure performed, preparing the patient for local anesthesia may or may not be similar to preparing the patient for general anesthesia. For example, administering a local anesthetic for dental surgery or for suturing a small wound may require that the nurse explain to the patient how the anesthetic will be administered, take a patient's allergy history, and when applicable, prepare the area to be anesthetized, which may involve cleaning the area with an antiseptic or shaving the area. Other local anesthetic procedures may require the patient to be in a fasting state because a sedative may also be administered. The nurse may administer an intravenous sedative such as the antianxiety drug diazepam (Valium) (see Chap. 30) during some local anesthetic procedures, such as cataract surgery or surgery performed under spinal anesthesia.

General Phenotype of Tac1Null Mutant Mice

Two independent tac1 -null mutant mouse strains have been described, originally on a mixed 129 SvxC57BL 6J (Zimmer et al. 1998) or CD1XC57BL 6J (Cao et al. 1998), and later another on a pure C57BL 6J genetic background (Bilkei-Gorzo et al. 2002). The first reports (Cao et al. 1998 Zimmer et al. 1998) showed altered pain reactivity in tac1-deficient mice. The pain sensitivity of tac1 ' mice on a C57BL 6Jx129 Sv genetic background was reduced in the hot-plate test, but not in another thermal-pain model, in the tail-flick test. Thus, while spinal pain reflexes as measured in the tail-flick test were normal, supra-spinal pain responses as measured in the hot-plate test seemed to be reduced in the absence of SP. Basbaum reported that the pain phenotype in the hot-plate test was intensity dependent hypoalgesia was present using 55.5 C but not lower (52.5 C) or higher (58.5 C) plate temperatures (Basbaum 1999). Tac1- - mice on the mixed C57BL 6J genetic background were less reactive to...

Overview of motor systems

The most prominent feature of CB1 cannabinoid receptor distribution in the brain is its high level of expression in areas involved in the control of movement, which is consistent with the effects of cannabinoids on movement (Glass et al., 1997 Fride et al., 1995 Herkenham et al., 1991a,b,c Mailleux and Vanderhaeghen, 1992 Pettit et al., 1998 Romero et al., 1995,1996a,b Sanudo-Pena et al., 1999a Sulcova et al., 1998 Tsou et al., 1998a). No cannabinoid receptors are found in striate muscle. The brain areas with the highest levels of cannabinoid receptors include the basal ganglia and the cerebellum, classically referred to as the extrapyramidal motor system. The basal ganglia together with the vestibulo-cerebellar system are implicated in the maintenance of muscle tone and equilibrium where they basically exert opposite actions. Together, they provide an adequate basal state for movement to occur. Also, moderate levels of CBX binding exist in what was originally called the pyramidal...

Endogenous Opiate Receptor Ligands

It appears that the enkephalins are not metabolic products. There is likely a single P-endorphin system associated with lipotropin within cell bodies in long axons innervating the midbrain and limbic system. Enkephalin-containing cells and nerves were found throughout the brain and spinal cord. Enkephalin-rich areas appear to coexist with dopaminergic, noradrenergic, serotonergic, and substance-P neuronal systems. Opiate receptors and enkaphalin-containing fibers show a parallel distribution in many areas. There are considerable enkephalinergic fibers in the gastrointestinal tract, where a 17-amino-acid peptide has been discovered in the pig duodenum. These findings further explain the effectiveness opiates have in the treatment of diarrhea and dysentery. There may be real and potential clinical relevance as well (e.g., the area of addiction and possible development of new analgetics, including synthetic analogs of the enkephalins themselves) (see Table 5-7).

General Information

In a randomized, double-blind study, 64 patients undergoing total knee arthroplasty received either intrathecal morphine 0.3 mg or intrathecal diamorphine, 0.3 mg in 0.3 ml, with 2-2.5 ml of 0.5 heavy spinal bupivacaine (3). The patients given morphine had significantly greater analgesia at 4, 8, and 12 hours postoperatively. The incidence of opioid-related adverse effects was not significantly different between the groups. In a single-blind, randomized, controlled study, 70 patients scheduled for elective cesarean section under spinal anesthesia using hyperbaric bupivacaine 0.5 received intrathecal fentanyl 20 mg, intrathecal diamorphine 300 mg, or 0.9 saline (4). Significantly less intraoperative and postoperative ''analgesic control'' was required in the opioid groups, especially in those given diamorphine. Diamorphine produced longer-lasting analgesia than fentanyl (12 hours versus 1 hour). Nausea, vomiting, and pruritus occurred relatively infrequently, with no differences...

Ergotamine and dihydroergotamine

Ergotamine and dihydroergotamine have been used in preventing migraine attacks and dihydroergotamine in the treatment of hypotension (either orthostatic or caused by spinal or epidural anesthesia). When dihydroergotamine was given intravenously after coronary bypass surgery, despite increased filling pressure there was no rise in cardiac output, and despite increased cardiac work the bypass flow fell significantly. The significant decrease in regional myocardial vascular resistance found after the administration of dihydroergotamine may explain the absence of the expected increase in cardiac output and coronary bypass flow.

Synaptic Effects Of Exogenous Cannabinoid Ligands

Cannabinoid agonists also inhibit glutamate release throughout the CNS. To date, this effect has been demonstrated in the hippocampus (Shen et al., 1996 Sullivan, 1999), the dorsolateral and ventral striatum (Gerdeman and Lovinger, 2001 Robbe et al., 2001), the cerebellum (Levenes et al., 1998 Takahashi and Linden, 2000), the substantia nigra (Szabo et al., 2000), the prefrontal cortex (Auclair et al., 2000), and the spinal cord (Morisset and Urban, 2001). However, these effects have been more variable than those reported for GABA release in several respects. Whereas in some studies the cannabinoid-mediated inhibition of glutamate release is linked to the inhibition of VDCCs (Shen and Thayer, 1998 Sullivan, 1999), others have found that the inhibitory effects of WIN55212-2 on glutamate release are mediated by activation of a 4-aminopyridine-sensitive K+ channel (Robbe et al., 2001). Curiously, our own studies in the shell of the nucleus accumbens found no evidence for presynaptic...

Protection against infection

In contrast to the body of data indicating that cannabinoids exacerbate host resistance to infection, it has been reported that cannabinoids have the potential to exert protective effects for select pathological conditions. Gallily et al. (1997) indicated that Dexanabinol (HU-211), a synthetic non-psychotropic cannabinoid, improved neurological outcomes in rodent models of brain trauma, ischemia, and meningitis. HU-211 was shown to suppress TNFa production and to rescue mice and rats from endotoxic shock after lipopolysaccharide (LPS, Escherichia coli 055 B5) injection. Bass et al. (1996) tested the efficacy of HU-211 in combination with antimicrobial therapy in reducing brain damage in a rat model of pneumococcal meningitis. Streptococcus pneumonia-infected rats were treated with saline, ceftriaxone (100mg kg), or with a combination of ceftriaxone (100mg kg) and HU-211 (5mg kg intravenously). Brain edema and blood-brain barrier impairment were significantly (p 0.05) reduced for...

Fast Excitatory Neurotransmission

Activation of CB1 receptors inhibits the release of the excitatory neurotransmitter glutamate in many brain regions and in the spinal cord (Table 1). Spinal cord (cord slice) between primary sensory fibres and neurons in the dorsal horn of the spinal cord this effect could be the basis of the spinal analgesia produced by cannabinoids.

Drug Administration Drug administration route

Subarachnoid space via a lumbar puncture needle 3-5 ml of cerebral spinal fluid were withdrawn and mixed with 0.5, 0.7, 0.8, or 1 ml of gadopentetate dimeglumine. There were no significant behavioral changes, neurological changes, or seizure activity, but 19 patients had headache after lumbar puncture, 6 had nausea, and 2 had vomiting. All the adverse effects resolved within the first 24 hours with bed rest.

Receptor for Myorelaxation

The muscle relaxant effect of diazepam is largely mediated by a2 GABAA receptors, as shown by the failure of diazepam to induce changes in muscle tone in the a2 point-mutated mouse line (Crestani et al. 2001). a2 GABAA receptors in the spinal cord, notably in the superficial layer of the dorsal horn and in motor neurons (Bolhalter et al. 1996), are most likely implicated in this effect. The muscle-relaxant effect requires considerably higher doses of diazepam than its anxiolytic-like activity, which is mediated by a2 GABAA receptors located in the limbic system (see above). It was only at very high doses of diazepam that a3 and a5 GABAA receptors were also implicated in mediating myorelaxation (Crestani et al. 2001 Crestani et al. 2002).

Other Endocannabinoid Targets TRP Channels

In all of the above studies, endocannabinoid signalling is mediated largely via presynaptic activation of cannabinoid CB1 receptors. However, endocannabinoids such as anandamide have some affinity for other receptors, such as the TRPV1 'noxious heat capsaicin' receptor (Di Marzo et al. 2001). Besides their predicted primary afferent localisation, TRPV1 receptors are present within discrete brain regions (Sasamuraet al. 1998 Mezey et al. 2000). Thus, in addition to CB1 -mediated presynaptic effects, exogenously applied anandamide acts via TRPV1 receptors to increase spontaneous glutamatergic synaptic transmission not only within the spinal and medullary dorsal horn (Morisset et al. 2001 Jennings et al. 2003) but also within brain regions such as the hippocampus and substantia nigra (Al-Hayani et al. 2001 Marinelli et al. 2003) (Fig. 3A).

Carbonic Anhydrase Activity Suppressing Diuretics

Symptoms for using carbonic anhydrase inhibitors are edema in cardiopulmonary insufficiency, glaucoma (wide angle, secondary, and preoperational narrow-angle glaucoma), minor epileptic attacks, premenstrual high blood pressure, and severe altitude sickness. It is believed that in glaucoma, the effect of drugs is possibly linked to suppression of carbonic anhydrase in ciliary bodies, which can result in decreased secretion of cerebrospinal fluid. Of the drugs that suppress carbonic anhydrase activity, acetazolamide, methazo-lamide, and dichlorphenamide are used in medical practice.

Dominant Pharmacological Characteristics

The rate of clearance of LSD from blood (solid line) and cerebrospinal fluid (broken line) of the monkey after a dose of 200 g kg administered intravenously. Reproduced by permission from Axelrod et al, 1957. Fig. 5. The rate of clearance of LSD from blood (solid line) and cerebrospinal fluid (broken line) of the monkey after a dose of 200 g kg administered intravenously. Reproduced by permission from Axelrod et al, 1957. Exclusive of protein binding, LSD seems to be distributed throughout the body water with little impedance by anatomic barriers. Figure 5 (Axelrod et al., 1957) shows the rate of clearance of LSD from the blood and cerebrospinal fluid (CSF) of the monkey after 200 g kg given intravenously. Since the amount of drug present in the cerebrospinal fluid was about the same as the

N Arachi Do Noy Lg Lycin E

One putative pathway for the synthesis of Af-arachidonoylglycine is the oxidative metabolism of anandamide via alcohol dehydrogenase (Burstein et al., 2000). Though this pathway may exist, it is clear that . V-arachidonoylglycine is also synthesized from the precursors arachidonic acid and glycine (Huang et al., 2001). The compound is degraded by FAAH and displays higher potency as an FAAH inhibitor than anandamide. Among the tissues analyzed, the highest levels were present in the brain, spinal cord, small intestine, kidney, and skin (Huang et al., 2001). In addition to N-arachidonoylglycine, other arachidoloyl amino acids have been found in the brain, including N-arachidonoyl-gamma-aminobutyric acid (GABA) and A'-arachidonoylalanine (Huang et al., 2001). Tissues that are known to express COX-2, including the brain and spinal cord, contain high levels of . V-arachidonoylglycine. Although this compound is resistant to metabolism by COX-1, COX-2 metabolites of . V-arachidonoylglycine...

HIV protease inhibitors

The effect of ketoconazole (200 and 400 mg qds) on plasma and cerebrospinal fluid concentrations of ritonavir (400 mg bd) and saquinavir (400 mg bd) have been investigated in a two-period, two-group, longitudinal pharma-cokinetic study in 12 HIV-infected patients (44). Ketoconazole significantly increased the AUC and trough concentrations of ritonavir and prolonged its half-life (by 29 , 62 , and 31 respectively). It produced similar changes (37 , 94 , and 38 respectively) in the kinetics of saquinavir. Ketoconazole significantly increased the ritonavir CSF concentration at 4-5 hours after the dose by 178 (from 2.4 to 6.6 ng ml), with no change in the paired unbound plasma concentration (26 ng ml). The changes were not related to ketoconazole dose or plasma exposure. The corresponding changes in saquinavir CSF concentrations were not significant. The authors concluded that ketoconazole inhibited the systemic clearance of ritonavir and, because of the disproportionate increase in CSF...

Brain Structures And Drugs

Information processing includes sensory information that comes in from sense organs (e.g., eyes, ears, tongue) to the brain through the spinal cord or directly through cranial nerves (nerve cells connected directly to the brain). This incoming information from sense organs goes to a central relay station called the thalamus. The thalamus is specialized, much like the cerebral cortex, in that defined areas receive input that is specific to a sensory modality. For example, input from the eyes through the optic nerve goes to a region of the thalamus called the dorsal lateral geniculate nucleus. This area of the thalamus, in turn, sends the information transmitted from sense organs to the appropriate primary sensory area of the cortex. For example, the lateral geniculate sends visual information to the area of the cortex specialized for vision, which is located in the occipital lobe. Similarly, the cerebral cortex sends commands to the effector systems (usually muscles) that...

Precursors of Acetylcholine

Adequate availability of choline has been proposed to enable sufficient ACh (1) synthesis for neurotransmission. Precursors of ACh (e.g. choline and lecithin) have been investigated for their effects on synthesis and release of ACh, with a view to increasing ACh release and cholinergic activity. Few clinical or animal studies have reported any significant beneficial effects on cognitive function with these compounds 8 . Therapy failure may be due to impaired uptake mechanisms of choline causing the reduction in ACh synthesis, and not due to insufficient choline supply. This is apparent as it has been reported that more choline occurs in the cerebrospinal fluid of AD patients than in patients without AD, and that choline levels increase with disease progression 8, 19 . Therapy with ACh precursors may be limited by side-effects, including gastrointestinal disturbances such as nausea, vomiting and diarrhoea.

Biological Evidence For A Role Of The Endocannabinoidcb Receptor System In Neuropsychiatry Disorders

Thus far, only a few studies have been performed on the putative connection between the endocannabinoid-CBj receptor system and schizophrenia in humans. Higher concentrations of CBj receptors have been found in the dorsolateral PFC of deceased schizophrenic patients but not in other regions such as the hippocampus and the caudate-putamen (Dean et al., 2001). Levels of anandamide were higher in the cerebrospinal fluid of schizophrenic patients, but only in 3 out of 10 patients (Leweke et al., 1999). In the same study, an elevation of the non-CB1 receptor-binding palmitoyl ethanol amide was also found in a subset of 4 of the 10 patients. It seems that only an analysis of both these findings combined produced statistical significance (Leweke et al., 1999). Further, healthy volunteers intoxicated with cannabis resin displayed perceptual abnormalities similar to that of schizophrenic patients who did not receive cannabis (Emrich et al., 1997). This observation was interpreted as support...

Descending Modulation of Pain 131

That this analgesic phenomenon could be reversed by naloxone, suggesting that the electrical stimulation releases an endogenous opiate-like substance that led to analgesia. These observations set the stage for extensive studies of how the PAG can entirely block pain sensations (reviewed by Fields et al. 1991). It became clear that this occurs through projections from the PAG to the rostral ventromedial medulla (RVM), and from there to the spinal cord. Specific on- and off-cells in the RVM were found to control the excitability of ascending spinal pathways. On-cells fire just before a nocifensive flexion reflex and off-cells, which are spontaneously active, stop firing just before a nocifensive flexion reflex. This pathway is activated by certain forms of stress and appears to naturally serve to control the organism's response to noxious stimuli, being able to entirely suppress pain under certain conditions. More recently, it has become clear that the RVM can facilitate as well as...

Implications for Understanding Cannabinoid Actions in Pain

The above outline of current understanding of the neural processing that underlies pain provides a foundation for understanding the effects of exogenous and endogenous cannabinoids in pain. Cannabinoids act at all of the sites discussed above, i.e., the periphery, spinal cord, and central circuits for pain facilitation and pain modulation. In the following sections, we review the current understanding of the systemic effects of cannabinoids and their sites of action within pain processing circuits from anatomical, physiological, and behavioral perspectives.

Antinociception and Suppression of Pain Neurotransmission by Systemically Administered Cannabinoids

In part to address this potential confound, subsequent electrophysiological and neurochemical studies examined the question of whether cannabinoids suppress activity within pain circuits. These studies provided convincing evidence that cannabinoids suppress nociceptive transmission in vivo (see Hohmann 2002 for review). Walker's laboratory first demonstrated that cannabinoids suppress noxious stimulus-evoked neuronal activity in nociceptive neurons in the spinal cord (Fig. 2)

Membrane Signaling And Volume Transmission

The terms wiring transmission (WT) and VT were introduced to provide a systematic categorization of intracellular communication in the brain (Zoli et al., 1999). Wiring (voltage) transmission (WT) is a well defined quantifiable entity, while VT is not as clearly delineated. VT refers to hormonal messengers in brain extracellular space and cerebrospinal fluid. In the membrane bilayer signaling, VT might also occur and be more clearly defined. A signal transmission by a signaling lipid ligand occurring in the fluid milieu of the lipid bilayer will induce a volume change. This change in the lipid bilayer volume is imparted through VT of the lipid signaling molecule to the 7TM receptor protein, and in turn affects the volume of the receptor. A change in receptor volume will result in an adiabatic amplification of the original signal the pressure volume relationships of the protein would be modulated by the recycling of the natural physiological lipid ligand AEA. Signaling through the...

Methodological Considerations

CBRs have been studied in rat spinal cord using autoradiographic (Herkenham et al. 1991 Hohmann et al. 1999a Hohmann and Herkenham 1998) and immunocytochemical (Farquhar-Smith et al. 2000 Morisset et al. 2001 Salio et al. 2002b Salio et al. 2001 Sanudo-Pena et al. 1999 Tsou et al. 1998a) techniques. It is important to note that localization studies employing antibodies raised against the N-terminal of the CB1R protein may reveal different patterns of immunostaining from antibodies raised against the C-terminal tail and support different conclusions regarding the anatomical localization of CBRs. Antibodies recognizing the intracellular C-terminal domain of CB1R might be expected to behave differently depending on the level of tissue fixation and receptor internalization. It is possible that N-terminal antibodies underestimate localization of CB1R to plasma membrane and primarily reflect synthesis, storage, or transport sites detection of CB1R at the plasma membrane would require an...

Peripheral CB1RMediated Antinociception Acute and Persistent Pain States

The development of carrageenan-evoked mechanical hyperalgesia, allodynia, and spinal Fos protein expression (Nackley et al. 2003b) these latter actions were completely blocked by coadministration of either a CB1R or CB2R antagonist. Cannabinoids induce a site-specific topical antinociception to thermal stimulation (Dogrul et al. 2003 Johanek and Simone 2004 Ko and Woods 1999 Yesilyurt et al. 2003). This local antinociceptive effect synergizes with spinal cannabinoid antinociception, as reflected by a 15-fold leftward shift in the dose-response curve (Dogrul et al. 2003), and also synergizes with topical morphine antinociception (Yesilyurt et al. 2003). The latter effects were blocked by a CB1R antagonist (Yesilyurt et al. 2003). A role for CBIRs in suppressing hyperalgesia and allodynia induced by nerve injury has been demonstrated in multiple models of neuropathic pain (Bridges et al. 2001 Fox et al. 2001 Herzberg et al. 1997 Mao et al. 2000). Fox and colleagues demonstrated that...

Drug Drug Interactions Diclofenac

Although spinal morphine provides effective analgesia, different ways of managing and minimizing its troubling adverse effects are constantly sought. Diclofenac, a non-steroidal anti-inflammatory drug, improves the analgesia provided by epidural morphine and may allow dosage reduction. In an investigation of this drug combination, intrathecal morphine was administered either regularly or on demand to 120 women undergoing cesarean section in doses of 0.1 mg, 0.05 mg, or 0.025 mg with diclofenac 75 mg intramuscularly (53). Severe pruritus was significantly more common in those who received morphine 0.1 mg and there was a trend toward less vomiting with smaller doses. There was no respiratory depression. The results suggested that the adverse effects of intrathecal morphine are dose-dependent and that there was no advantage in using doses of morphine larger than 0.25 mg.

Pharmaceutical interest

Strychnine The seeds of Strychnos nux-vomica L. are toxic due to the presence of strychnine, an indole alkaloid first characterized in 1817 by Pelletier and Caventou. Strychnine was formerly used to stimulate blood circulation in surgical shock, but its use is now more restricted to promoting breathing in poisoning cases, as in small doses, it enhances the motor response of the spinal reflex. Nux Vomica (British Pharmacopoeia, 1963) consists of the dried ripe seeds containing not less than 1.2 of strychnine. It was used in Western medicine as a bitter tonic and as an ingredient in purgative pills and tablets. The seeds of Strychnos nux-vomica L. are used Warning In regard to the toxic effect of Nux Vomica, ingestion of a single seed will cause tremors and slight twitching of the limbs, followed by sudden convulsions of all the muscles. The body becomes arched backwards in hyperextension with the legs and arms extended, and the feet turned inwards. The facial muscles produce a...

Distribution of CBRs on Central Terminals of Primary Afferents

Receptors are typically bidirectionally transported from the soma to central and peripheral terminals (Young et al. 1980). To identify afferents likely to contain CBRs, Hohmann and Herkenham assessed their pre- and postsynaptic distributions in the spinal cord using receptor binding and quantitative autoradiography (Hohmann et al. 1999a Hohmann and Herkenham 1998). Destruction of sensory C fibers with neonatal capsaicin treatment produced only modest (16 ) decreases in cannabinoid binding sites in the superficial dorsal horn, as measured by receptor binding and quantitative autoradiography (Hohmann and Herkenham 1998). These data suggest that a majority of spinal CBRs is not localized to central terminals of primary afferent C fibers. Multisegment unilateral cervical dorsal rhizotomy (C3-T1 or T2) produced time-dependent losses in cannabinoid binding densities in the dorsal horn (Hohmann et al. 1999a) of larger magnitude than that induced by neonatal capsaicin treatment. This...

Serotonin Dopamine And Norepinephrine Psychedelic Messengers

Serotonin is a neurotransmitter that regulates sleep, pain sensation, appetite, mood, sensory perception, aggression, memory, and body temperature it often plays a role in helping us feel relaxed and at ease. The nerve cells that release serotonin are localized in a section of the brain called the raphe nuclei, which is located in the brain stem and lies just at the top of the spinal cord. The brain stem controls our autonomic processes, including, for example, breathing, heart rate, and blood

Role of the Periaqueductal Gray

Studies of metabolically stable anandamide analogs and the effects of anandamide in FAAH knockout mice lead to the conclusion that anandamide would produce antinociceptive effects upon release in the appropriate brain, spinal, or peripheral sites. Electrical stimulation of the dorsal aspect of the periaqueductal gray (PAG) caused CBlR-mediated analgesia evidenced by a markedly reduced effect following administration of SR141716A (Walker et al. 1999). This work suggested that the dorsal PAG serves as a substrate for cannabinoid antinociception. Exogenously applied cannabinoids have been shown to inhibit GABAergic and glutamatergic neurons in rat PAG neurons through presynaptic mechanisms (Vaughan et al. 2000). These effects occurred in the absence of direct postsynaptic actions on PAG neurons, thus providing a neurophysiological basis for cannabinoid modulation of nociceptive transmission through presynaptic actions.

Established Neurotransmitters Of The

The gastrointestinal tract (GIT) is in a state of perpetual contractile and secretory activity. The patterns of motility of the GIT include mixing and propulsive movements that are confined to regions and organized patterns of movement such as swallowing and esophageal peristalsis, migrating complexes, vomiting, and defecation, which involve large sections of the digestive tract (Olsson and Holmgren, 2001 Thomson et al., 2001). These activities are controlled in part by the muscle itself, the local enteric nervous system (ENS), and by the central nervous system (CNS) acting via both autonomic (sympathetic and parasympathetic) and somatic innervation as well as humoral pathways. However, basically, most functions of the intestine are autonomous and are largely controlled by the ENS (Kunze and Furness, 1999). The ENS lies entirely in the wall of the gut, beginning in the esophagus and extending all the way to the anus. The number of neurons in the enteric system is approximately 100...

Nerveimpulse transmission simplified

All nerve impulses, whether sensory (incoming) or motor (outgoing) are transmitted via either the peripheral or the central nervous system (PNS CNS). The central nervous system is composed of bundles of nerve fibers that make up the spinal chord and part of the brain. Peripheral nerves are those outside of the brain and spinal chord, in the arms, legs and organs. Nerve impulses are chemically and electrically carried along nerve fibers to and from the brain and spinal chord. Individual nerve cells are called neurons. There is a space between each nerve cell, called a synapse. The synapse separates the end of one neuron from the beginning of the next. Nerve impulses move rapidly across the synapse in response to chemical neurotransmitters. Neurotransmitters are released by one neuron cell, move across the synapse and fit into specific sites called receptor sites on the next neuron. Receptor sites come in many different shapes, allowing many different chemical signals to activate the...

Pregnancy Category C

Morphine can make people drowsy, so they should avoid operating an automobile or other hazardous machinery until they know how the drug affects them. Despite morphine's safety in a medical context, it can be hazardous when injected into fluid circulating through the spinal cord and brain, and if hospital staffs use this technique, they are advised to have resuscitation equipment on hand.

CB2RMediated Antinociceptive Effects

Electrophysiological studies also support a role for CB2Rs in suppressing nociception. AM1241 induced CB2R-mediated suppression of C fiber-evoked responses and windup in spinal WDR neurons this suppression was observed in both the absence and presence of carrageenan inflammation and following local and systemic drug administration (Nackley et al. 2004). The suppressive effects of AM1241 were more pronounced in the presence compared to the absence of inflammation. By contrast, low threshold, purely non-nociceptive spinal neurons did not show sensitization during the development of inflammation and were not altered by AM1241 actions in the periphery (Nackley et al. 2004). Intraplantar administration of anandamide also suppresses mechanically evoked responses in spinal dorsal horn neurons in the carrageenan model of inflammation these effects were blocked by a CB2R-selective antagonist (Sokal et al. 2003). These data demonstrate that activation of peripheral cannabinoid CB2Rs is...

Peripheral Neuropathy

One patient with anaesthesia dolorosa of her face, a condition that can occur after therapeutic damage to the trigeminal nerve, seems to have been cured of her problem. The severe burning, thumping pain that she experienced in her face was uncontrollable with analgesics and a range of psychotropic drugs. Not only did her pain recede completely but she was able to wean herself off all her medication. At 15 months she also discontinued nabilone and a year later has not had any recurrence of the pain in her face. She still has numbness though. Unfortunately, at the point at which nabilone was discontinued, she was discovered to have a metastatic carcinoma of the kidney. There is no evidence that this is anything more than coincidental. She subsequently went on to use nabilone to control the pain from a metastatic lesion in her spine (see below).

Physiology and Pharmacology

6.2.4 Causes of Erectile Dysfunction. Erectile dysfunction can result from neurological, vascular, hormonal, or psychological factors, or from a combination of two or more of these factors. Neurological causes include spinal cord injury, multiple sclerosis, or any other condition that impedes the transmission of the neural signal generated by psychogenic stimulation. Vascular causes include arterial insufficiency, which results in low arterial pressure delivered to the penis, and venous insufficiency, in which excessive venous outflow occurs because of inadequate compression of the subtunical venules. Erectile dysfunction of hormonal origin results from inadequate androgenic stimulation of the sexual center in the anterior hypothalamus, which lowers libido and hence erection quality. In psychogenic erectile dysfunction, sexually inhibiting psychological issues can impede

Regulation of Endocannabinoids by Fatty Acid Amide Hydrolase

FAAH is also found in Lissauer's tract, which comprises primary afferent fibers entering the spinal cord, and in small neurons in the superficial dorsal horn, which is the termination zone of nociceptive primary afferents. These observations demonstrate that a mechanism capable of inactivating anandamide, 2-AG, and NADA is present in regions of the CNS related to nociceptive processing and thus suggest a role for these ligands in pain modulation. Of course, the presence of FAAH does not necessarily identify that cell as a site of synthesis of endocannabinoids, as FAAH is a catabolic enzyme and also metabolizes fatty acid amides that act through CBR-independent mechanisms.

Central Neurogenic Pain

A patient who was tetraplegie following a spinal injury, had some benefit from nabilone. Previously he was smoking cannabis to control pain in his scapula region and in his sacral dermatomes. However, he achieved much better pain control for his distal body pain from regular cannabis use and consequently opted to continue smoking.

Effects of Endocannabinoids Assessed with CBR antagonists

Studies of the effects of SR141716A, a specific cannabinoid CB1R antagonist (reviewed by Walker et al. 2000) suggest that endocannabinoids participate in endogenous pain modulation and that this action involves the PAG. Blocking the cannabinoid CB1R with SR141716A produced hyperalgesia in the formalin test (Calignano et al. 1998 Strangman et al. 1998) and blocked the analgesia produced by electrical stimulation of the dorsolateral PAG (Walker et al. 1999). These findings are in line with previous studies (Richardson et al. 1997 Richardson et al. 1998b) that demonstrated hyperalgesia following intrathecal administration of this cannabinoid antagonist or CB1R knockdown with an antisense oligonucleotide. Chapman (1999) found that spinal nociceptive neurons exhibit markedly greater C fiber-mediated responses followinglow doses of SR141716A (0.1-1 ng in 50 ml applied to spinal cord). The authors of these studies posited that the pain-enhancement by the antagonist results from the blockade...

Second Generation Effects Pregnancy

In 30 women randomized to receive either sufentanil 7.5 micrograms plus bupivacaine 2.5 micrograms, with or without clonidine 50 micrograms, using a combined spinal-epidural technique, analgesia was prolonged in those given clonidine without an increased incidence of adverse effects or worse pain scores (87).

No of patients treated

Erectile dysfunction in spinal cord lesion Erectile function Papaverine nitrogylcerin 21509 Renganathan R, Suranjan B, Kurien T. Comparison of transdermal nitroglycerin and intracavernous injection of papaverine in the treatment of erectile dysfunction in patients with spinal cord lesions. Spinal Cord. 1997 Feb 35(2) 99-103. English

The cannabinoid receptor is discovered

After intravenous injection, Meng recorded the activity of specific neurons (nerve cells) in this cannabinoid receptor system and determined that cannabinoids reduce the pain signal transmission from the site of injury and up through the spinal chord. Cannabinoids do this by binding to pain receptors. He also determined that the cannabinoid receptor system works independently from opioid receptor system, by injecting antagonists 2 to both opioids and cannabinoids to see if the analgesic effect of one was diminished by the other. Meng recorded the activity of specific neurons (nerve cells) and determined that cannabinoids reduce the pain signal transmission from the site of injury and up through the spinal chord.

Barriers And Obstacles To Cns Drug Delivery Physiological Barriers

There are several physiological or pathological factors preventing systemic drug delivery to CNS, including the BBB and the blood-cerebrospinal fluid barrier (BCB). Of these, the BBB is the most important barrier in the drug transport process. The BBB can be defined as a physiological mechanism that alters the permeability of brain capillaries so that the majority of substances are prevented from entering brain tissue, although some molecules are allowed to enter freely. In the late 19th century, the German bacteriologist Paul Ehrlich observed that the certain dyes administered intravenously to small animals stained all the organs except the brain. His interpretation for the experiment was that the brain had a lower affinity for the dye than the other tissues. However, Edwin E. Goldmann, a student of Ehrlich, injected the dye trypan blue directly into the cerebrospinal fluid of rabbits and dogs. He found that the dye readily stained the entire brain but did not enter the bloodstream...

Anticonvulsant effects

The anticonvulsant uses of cannabis were reported several decades ago (Loewe and Goodman, 1947). Subsequent investigations in various animal species have confirmed and increased our understanding of this action. Turkanis and Karler, 1985 reported that cannabinoids induced a reduction of cortical-evoked response and spinal monosynaptic reflexes which corresponded to a decrease in neurotransmission. They postulated several possible biochemical mechanisms for the effect, including altered neurotransmitter release, altered transmitter equilibrium potential, and drug receptor interactions. So far, the mechanism of this action remains unclear.

Drug Administration Drug formulations

Nicolau syndrome (embolia cutis medicamentosa) is a very rare complication of intramuscular injections, in which there is extensive necrosis of the injected skin area, perhaps due to accidental intra-arterial and or para-arterial injection (233). It usually occurs in children in a review of 102 patients, 80 were under 12 years of age (234). Complications can include everything from an ischemic syndrome with local necrosis of the skin, subcutaneous tissue, and muscle, often combined with vascular and nervous system involvement, intestinal and renal hemorrhage, necrosis of the entire leg, and even paraplegia from spinal cord damage (235-241). Necrosis of the forearm has been described in two patients after inadvertent intra-arterial administration of dicloxacillin (242).

Susceptibility Factors Renal disease

In 40 patients undergoing prostatectomy with spinal anesthesia with lidocaine 5 (75 mg) intrathecally, either alone or co-administered with pethidine 0.15 or 0.30 mg kg, the higher dose of pethidine reduced the requirement for parenteral analgesics with a non-significant incidence of pethidine-related adverse effects (22).

Cannabis Use in Chronic Pain

Many patients self-report their use of cannabis for the relief of their chronic pain and a record of these has been kept recently. Two specific observations have been made. Firstly, a significant number of these patients have spinal pain as a result of trauma. The injuries have never been severe enough to cause neurological damage. However, all have experienced soft tissue damage and including one with a vertebral crush fracture. A common feature has been a combination of muscle spasm, excessive superficial spinal tenderness (hyperalgesia, allodynia) and lack of sleep.

Recording techniques Slice preparation

Standard recording techniques in adult rat hippocampal slices (350 im thick) were used as described previously (Stella et al., 1997 Schweitzer, 2000). The slices were submerged and superfused at a constant rate in gassed artificial cerebrospinal fluid (ACSF) of the following composition in mM NaCl, 130 KCl, 3.5 NaH2PO4, 1.25 MgSO4, 1.5 CaCl2, 2.0 NaHCO3, 24 glucose, 10. Drugs were dissolved in 0.1 DMSO.

Antioxidant Scavanger Action

The treatment of lumbar spinal cord ischemia may have very important clinical implications. Mechirova and Domorakova 31 have shown reasonable neuroprotective effects of EGb by histochemical analysis of NADPH-diaphorase activity (NOS-like activity) on segments of the lumbar spinal cord in rabbit subjected to 30 min ischemia and 24 h reperfusion. Reduction of reperfusion damage has been observed and was based on the scavenging activity of EGb towards free radicals produced during ischemia reperfusion (I R) of the spinal cord. The number of NADPH-d-positive neurons in sections of the L5 segment of the spinal cord was elevated in the ischemic spinal cord and rabbits expressed complete paraplegia. Pretreatment by EGb for 7 d caused disappearance of paraplegia, and NADPH-d activity in blood vessels and neurons was observed, similar to the controls. The authors proposed

Comments And Conclusions

It is now an established principle of neurophysiology that complex control systems are continuously in operation in shaping, blocking or facilitating one or another channel of sensory information, and that this regulation of sensory input to the brain is variable under different conditions of sleep and wakefulness. Such mechanisms for controlling afferent input not only permit focussing of attention to a particular task or motor event, but also protect the brain from the cacophonous interplay of the varied meaningless signals that continually bombard sensory receptors. Recent neurophysiological investigations indicate that much of the control of sensory input to the brain is regulated by projection pathways from nonspecific reticular systems to primary sensory neurons in the spinal cord and brain stem. Little imagination is required to envision the consequences of disturbances initiated by LSD in these reticular systems, hence the emphasis placed here on those experimental studies...

Survey Of Serotonergic Neuronal Systems In The Brain

An overview of the anatomic organization of 5-HT projections in the brain is useful as background for understanding the actions and toxicity of psychotropic amphetamines. Important features of 5-HT neurons are the diversity of cell types in multiple raphe nuclei and the specificity of their organization. Serotonergic neurons, first demonstrated by the histofluorescence method (Falck et al. 1962), are restricted to the brain stem, where they are localized in multiple discrete clusters along the midline, primarily within neuronal cell groups designated as the raphe nuclei (Taber et al. 1960 Dahlstrom and Fuxe 1964). These serotonergic nuclei extend from the midbrain to the caudal medulla and were originally described as nine cell groups, named B1 to B9, by Dahlstrom and Fuxe (1964). Serotonergic axon terminals have been found in widespread areas of the forebrain (including cerebral cortex, striatum, and diencephalon) (Fuxe 1965) and throughout the brain stem and spinal cord. A series of...

Ezio Carboni 1 Introduction

Microdialysis technique coupled with electrochemical detection (ED) is a relatively new method that allows detection of neurotransmitters and other substances from brain and other tissues. It is based on the insertion of a dialysis probe in a specific area and perfusing it with artificial cerebrospinal fluid (CSF), which, passing in a chamber delimited by the dialysis fiber, becomes enriched with small molecular weight substances diffusing into the fiber because of their concentration gradient. Substances recovered can be assayed by highperformance liquid chromatography (HPLC) to evaluate their concentration in the dialysate, that is closely related to their extracellular concentration in the area investigated. After recovery from surgery, therefore, the effects of drugs or other treatments on the assayed substance can be evaluated in freely moving animals (1).

Cardiovascular Effects Of Endocannabinoids Actions in vivo

Given the recent interest in endocannabinoids, attention has now turned towards their actions on the cardiovascular system. In this respect, exogenous anandamide, causes bradycardia (with secondary hypotension) and a transient pressor effect which is followed by a longer lasting depressor effect in urethane-anesthetized rats (Varga et al., 1995 Lake et al., 1997). This depressor effect was believed to be mediated by CBX receptor-dependent inhibition of sympathetic tone via a presynaptic mechanism, as the effect was independently attenuated by cervical spinal transection, -adrenoceptor blockade and cannabinoid receptor blockade. This sympatholytic action is greater in spontaneously hypertensive rats compared to normotensive controls, perhaps reflecting the higher level of sympathetic tone in the former (Lake et al., 1997). The pressor component of the response to anandamide was not sensitive to cannabinoid receptor blockade, perhaps reflecting a non CBX receptor-mediated response (Lake...

Placebocontrolled studies

In the Breast Cancer Prevention Trial (P-1), initiated by the National Surgical Adjuvant Breast and Bowel Project (NSABP) in 1992, more than 13 000 eligible women were randomized to tamoxifen 20 mg day or placebo for 5 years (12). During 69 months of follow-up tamoxifen reduced the risk of both invasive and non-invasive cancer and reduced fractures of the hip, radius, and spine however, the rate of endometrial cancer increased (RR 2.53 95 CI 1.35, 4.97), as did the frequency of vascular events.

Brief Physiology Of Pain

In the absence of injury, intense noxious stimuli trigger the activation of small diameter primary sensory neurons (A and C fibers) that have their receptive endings in the skin and the peripheral organs. This event subsequently activates two categories of spinal nociceptive neuron spinal wide dynamic range (which encode stimuli ranging from non-noxious to noxious) and nociceptive-specific neurons (which encode only noxious stimuli). The firing of these spinal nocicep-tive neurons leads to the activation of nociceptive circuits in the brain and ultimately, pain. In contrast, innocuous stimuli activate only large diameter primary sensory neurons (Afi fibers), which, via a pathway involving both non-nociceptive neurons and wide dynamic range neurons in the spinal cord and central som-atosensory circuits, signal only an innocuous sensation.

Peripheral Events In The Initiation Of Pain

Pain is initiated as activation of peripheral sensory fibres by injury or an insult to tissue but is perceived as a sensation through central responses. Thus, it may be relieved either by reducing its initiation by drugs acting peripherally or by drugs acting centrally to reduce the transmission and effects of nociceptive messages sent to the spinal cord and brain. Knowing the mediators involved in both the initiation and transmission of nociceptive impulses provides targets for drug therapy and pain control. The somatosensory primary afferent fibre, which conveys sensory information to the spinal cord, can be classified into several classes, according to the transduction properties of the individual nerve fibre. The properties of each afferent fibre are summarised in Table 21.1 and their termination sites in the spinal cord are shown in Fig. 21.1. The large diameter AyS-afferent fibre enters the dorsal horn of the spinal cord through the medial division of the dorsal root. It then...

Tachykinins and Substance P

The peptide tachykinins are widely distributed throughout the brain, spinal cord, and peripheral nervous system. Although research has primarily focused on pain and inflammation, it was well known that tachykinins are located in brain areas implicated in the pathophysiology of mood and anxiety disorders. Since its discovery in the 1930s, the 11 amino acid peptide substance P has been one of the most extensively studied neuropeptides. Its effects are mediated through G protein-coupled tachykinin (NK1) receptors, while neurokinin shows greatest affinity for the NK3 receptor. Substance P is frequently co-localized within neurons containing other neurokinins or neurotransmitters, such as GABA, dopamine, glutamate, 5-HT, and acetylcholine, often influencing their synaptic release (Otsuka and Yoshioka 1993).

CB1 Receptor Activated G Proteins and Effectors

Tolerance procedures have great utility for identifying signaling events that are uniquely specific to the pharmacological effects of cannabinoids. In particular, regional brain differences in the magnitude and time-course of downregulation and desensitization appear to occur concomitantly (Sim-Selley 2003). For example, the time-courses for development and recovery of tolerance that develops to cannabinoid hypothermia, hypomotility, antinociception, and memory impairment appear to be associated with CB1 receptor adaptation in hypothalamus, striatum, cerebellum, periaqueductal gray, spinal cord, and hippocampus. Plasticity of an endogenous system often occurs via phosphorylation events. It appears that the endocannabinoid system is no exception. Src tyrosine kinase and PKA are involved in tolerance to spinally mediated cannabinoid analgesia (Lee et al. 2003). Tolerance to THC was reversed with either an Src family tyrosine kinase inhibitor or a PKA inhibitor. Inhibitors of protein...

Interactions With Other Neurotransmitters

Some opioids, such as methadone and ketobemidone, have been reported to bind additionally to NMDA receptors and so may be different in their pharmacological profile. However, it is very unclear that this has any bearing on their effects in patients, especially in cases where morphine effectiveness is reduced, such as in neuropathic pain. In terms of changes in opioid systems relevant to the control of pain after nerve injury, nerve damage can lead to a loss of opioid receptors such as the marked reduction in spinal opioid receptor number seen after nerve section. Although this may be an explanation of the poor effectiveness of opioids in post-amputation pains, less severe nerve damage, where opioids can also lack effectiveness, only slightly alters opioid receptor number. However, the levels of the non-opioid peptide, cholecystokinin (CCK), can determine the potency of morphine and the peptide may, in turn, be upregulated after nerve damage. Activation of the CCKB receptor mobilises...

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