Peripheral Neuropathy Causes and Treatments

Peripheral Neuropathy Program By Dr. Randall Labrum

Peripheral Neuropathy Solution developed by Randall Labrum is a brand new program that provides people with an exclusive peripheral neuropathy treatment. In addition, this program introduces to people peripheral neuropathy causes, symptoms, and treatment plans for peripheral neuropathy. This program also covers safe remedies, exercises, diet plans, and step-by-step techniques that help people reduce their chronic peripheral neuropathy pain quickly within some minutes. Unlike other treatment protocols which just mask the symptoms and even danger your health with potential horrific side effects, this program is specifically designed to cure your own problem at its root cause. Neuropathy Solution Program using the very best risk-free treatment procedure to help your own body's build a capability to eliminate hurt and treat by natural means. With six easy steps that include changes in diet, exercise and lifestyle habits, a peripheral neuropathy sufferer can have permanent relief from the many painful, debilitating symptoms in as little as a month, often times even less. Continue reading...

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Peripheral Neuropathy

The pain arising from damage to peripheral nerves can be extremely difficult to control satisfactorily. Patients will commonly describe their pain as a constant burning, tearing or pricking sensation. Diabetic neuropathy is a good example and for some patients the use of tricyclic antidepressants or anticonvulsants is satisfactory. However, for others, these may be ineffective. Conventional analgesics are often of little use. Two patients with diabetic neuropathy achieved good pain relief with nabilone but only one continues to use it. The other has found that the dysphoric side effects interfered too much with her daily life. She therefore opted for less satisfactory pain relief, using tramadol. However, from a functional point of view, she was better.

Advances in Medical Cannabis Research

To develop novel cannabinoid medicines, supports an ongoing breeding project to develop high-yielding Cannabis cultivars of known cannabinoid profile. The aims of this research are to create varieties that produce only one of the four major cannabinoid compounds (e.g., THC, CBD, CBC, CBG, or their propyl homologs) as well as selected varieties with consistently uniform mixed cannabinoid and terpenoid profiles. These uniform profiles allow for the formulation of nonsmoked medicinal products, which can meet the strict quality standards of international regulatory authorities. A sublingual spray application of plant-derived THC and CBD began clinical trials for relief of multiple sclerosis-associated symptomology in 1999. These clinical trials have gone on to include patients with neuropathic pain and cancer pain.

Observational studies

It is therefore encouraging to read a report from Lima, Peru, where 60 patients from a shanty town tolerated a median of eight antituberculosis drugs fairly well for a median duration of 20 months (3). All received a parenteral aminoglycoside daily for 6 months, cycloserine, and a fluor-oquinolone, and most also took para-aminosalicylic acid and ethionamide. Of 60 patients, 23 took clofazimine, 23 pyrazinamide, 25 isoniazid, and 3 rifampicin. Commonly encountered adverse effects included dermatological effects, including bronzing of the skin (many of these patients were taking clofazimine and fluoroquinolones), depression, anxiety, and peripheral neuropathy. All complained of mild gastritis. There were no cases of serious hepatic or renal toxicity. This may have been because only a few patients took rifampicin. Absence of eighth nerve toxicity was striking, and can be attributed to close monitoring of patients by physicians with experience of DOTS-plus regimens.

Participation of the CB1 Cannabinoid Receptors in the Control of Pain

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. 1998), 2,4-dinitrobenzene sulphonic acid (DNBS)-induced colitis (Massa et al. 2004) and also in neuropathic pain models, such as the painful mononeuropathy induced by loose ligature of the sciatic nerve (Herzberg et al. 1997 Mao et al. 2000). Electrophysiological studies also provide evidence that cannabinoids attenuate nociceptive transmission in vivo (Pertwee 2001 Hohmann 2002). Thus, cannabinoids suppress noxious stimulus-evoked neuronal activity in nociceptive neurons in the spinal cord and thalamus (Hohmann et al. 1995 Martin et al. 1996 Tsou et al. 1996). There is increasing evidence to support a role for peripheral...

General Information

Although they are commonly used in the adjunctive management of chronic pain, benzodiazepines are generally not analgesic per se. One exception may be the stabbing lancinating neuropathic pain that often responds to anticonvulsants, including clonazepam. Nevertheless, the use of benzodiazepines in pain syndromes is generally contraindicated, and clonazepam, although often effective, should be used with caution (SEDA-17, 42). This is because of the availability of other agents with comparable or superior efficacy and the significant incidence of adverse effects of clonazepam, including depression, self-poisoning, cognitive impairment, and dependence (2), as well as the potential for diversion.

Pregnancy Category C

The drug was first isolated from coca plants in the mid-1800s. Cocaine apparently functions as an insecticide in the plants, but the substance has had no commercial agricultural use for that purpose. Early medical applications included administration to treat addiction to alcohol and opiates, but persons addicted to those drugs did not better on cocaine. Like many stimulants, cocaine has anorectic (weight-reducing) properties that decline as usage stretches over time but the drug's main medical use has been as a local anesthetic, particularly in ear, nose, and mouth surgery. Experimental use as an antide-pressant has been unsuccessful. Cocaine has been used to treat tonsillitis, earache, toothache, burns, skin rash, hay fever, asthma, hemorrhoids, nerve pain, nausea, and vomiting. It makes the body's immune system more active. For medical purposes cocaine has been largely superseded by drugs having less potential for abuse, but it is still called an excellent anesthetic for nose...

Adrenergic Sympathomimetic Drugs

The sympathetic nervous system plays an important role in the involuntary regulation of cardiac activity, vascular tonicity, functional activity of smooth muscle, and glands by releasing endogenic adrenergic substances, catecholines, from peripheral nerve endings into the synapses of the central nervous system (CNS).

General adverse effects

Body formation also occur and methemoglobinemia can be a problem at doses over 200 mg day. Agranulocytosis is rare but potentially fatal. Mild gastrointestinal complaints and neurological effects of dapsone are not uncommon. Under 0.5 of the patients taking prolonged dapsone therapy develop the dapsone syndrome (SEDA-16, 347). Other rare adverse effects include peripheral neuropathy, psychosis, hepatitis, nephritic syndrome, and renal papillary necrosis. Hypoalbuminemia has been seen after prolonged dapsone therapy of dermatitis herpetiformis (9). Erythema nodosum leprosum may be due to an immune complex mechanism the antigen is provided by the bacteria and their degeneration products, possibly as a kind of Jarisch-Herxheimer reaction (10). Anaphylactic shock and tachycardia are rare. Rashes, serious cutaneous reactions, and erythema nodosum may have an immunologi-cal basis. Tumor-inducing effects have not been reported.

Psychological psychiatric

The psychotomimetic effects of ketamine, apart from encouraging illicit use, can lead to distressing psychic disturbances, particularly in children (13) there can be nightmares, delirium, and hallucinations (25). Oral keta-mine is an effective analgesic in patients with chronic pain. In 21 patients with central and peripheral chronic neuropathic pain treated with oral ketamine, the starting dose was ketamine 100 mg day, titrated upward by 40 mg day increments every 2 days until a satisfactory effect was achieved, or until adverse effects became limiting (19). Nine patients discontinued ketamine because of intolerable adverse effects, including psychotomimetic symptoms, such as elevator'' effect or dissociative feelings, somnolence or insomnia, and sensory changes such as taste disturbance and somatic sensations.

Comparative studies

The safety and efficacy of lamivudine (300-600 mg day) in combination with zidovudine (600 mg day) in the treatment of antiretroviral-naive and zidovudine-experienced HIV-infected persons has been compared with zido-vudine monotherapy in two placebo-controlled studies of 129 and 223 patients (5,6). There were no significant differences in the incidence or severity of adverse effects between patients taking zidovudine alone or in combination with lamivudine. In both studies gastrointestinal symptoms, notably nausea, were the most commonly observed adverse reactions, occurring in 5-11 of zidovudine-experienced patients and 23-29 of antiretro-viral drug-naive individuals. Although one antiretroviral drug-naive patient taking combined therapy had an asymptomatic rise in pancreatic amylase activity, acute pancreatitis was not observed in either study. Grade 1 peripheral neuropathy was reported in one zidovudine-experienced patient taking low-dosage lamivudine (150 mg bd) and zidovudine.

Organs and Systems Nervous system

Melarsoprol given intravenously in patients with trypanosomiasis can cause a peripheral neuropathy within 2-5 weeks (SEDA-14, 243). It also causes a reactive arsenical encephalopathy in 3-5 of patients with trypanosomiasis (SEDA-13, 834) (6). Myalgia, distal paresthesia, and rapidly progressive weakness in all limbs developed in a young woman treated for 38 days with melarsoprol there was massive distal Wallerian degeneration in the peripheral nerve, and abnormalities in the dorsal ganglia and spinal cord. Very high concentrations of arsenic were found in the spinal cord. All the findings were typical of toxic arsenic accumulation in this case, renal dysfunction was probably at the root of the arsenic poisoning (SEDA-16, 316).

Descending Modulation of Pain 131

More recently, it has become clear that the RVM can facilitate as well as dampen pain (reviewed by Porreca et al. 2002). Stimulation of the RVM at relatively low current intensities increases the responses of spinal dorsal horn neurons to noxious stimuli. The role of this facilitation in chronic pain is suggested by studies showing that blockade of the RVM with lidocaine reduces abnormal tactile responses in rats with neuropathic pain (Pertovaara et al. 1996). Other studies of inflammatory and neuropathic pain converge in showing that descending facilitation is an important component of pathological pain.

Antinociception Mediated by CBIRs in the Periphery

The distribution of CBRs outside the central nervous system is consistent with behavioral and neurochemical data that implicate a role for peripheral CB1Rs in cannabinoid antinociception. The distribution of CB1Rs in dorsal root ganglia and peripheral nerve is therefore reviewed here. The role of CB2Rs in cannabinoid antinociceptive mechanisms is reviewed in Sect. 4. Traditionally, the dorsal root ganglion (DRG) has been used as a model of the peripheral nerve because of its more convenient size, location, and the ability to correlate cell size and neurochemical phenotype with peripheral axon caliber. Hohmann and Herkenham (1999a,b) used in situ hybridization to test the hypothesis that dorsal root ganglion cells, the source of primary afferent input to the

Axonal Transport of CBRs to the Periphery

We used 3H CP55,940 binding and high-resolution emulsion autoradiography to test the hypothesis that CBRs synthesized in dorsal root ganglion cells are transported to the periphery. Transport of CBRs to the periphery was occluded by tight ligation of the sciatic nerve (Hohmann and Herkenham 1999a). These data suggest that CBRs synthesized in the DRG are likely to undergo anterograde transport and be inserted on terminals in the peripheral direction (Fig. 3C, D). This observation is also consistent with the observation of CB1R immunoreactivity in rat peripheral nerve and in ventral roots (Sanudo-Pena et al. 1999). More work is necessary to determine if CBRs synthesized in the DRG are differentially transported to peripheral vs central terminals and whether transport of these receptors is modulated by persistent pain states.

Peripheral CB1RMediated Antinociception Acute and Persistent Pain States

Behavioral and neurochemical studies implicate a role for peripheral CB1Rs in cannabinoid antinociception in models of acute, inflammatory, and neuropathic pain states. Capsaicin-evoked CGRP release is enhanced in paw skin derived from rats with diabetic neuropathy induced by streptozotocin (Ellington et al. 2002). The mixed CBi CB2 agonist CP55,940 attenuated capsaicin-evoked CGRP release in diabetic and nondiabetic animals, and these effects were blocked by a CB1R but not a CB2R antagonist (Ellington et al. 2002). Interestingly, anandamide inhibited capsaicin-evoked CGRP release in nondiabetic but not in diabetic rat skin, but neither the CB1R nor the CB2R antagonist attenuated these effects. Functional changes following diabetic neuropathy may have prevented these inhibitory effects of anandamide on capsaicin-evoked CGRP release. Anandamide also increased capsaicin-evoked CGRP release at high concentrations, possibly through a TRPV1 mechanism, although susceptibility to blockade by...

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).

Antinociceptive and Electrophysiological Effects of Spinally Administered Cannabinoids

Spinal administration of a cannabinoid (HU210) also suppresses C fibermediated post-discharge responses, a measure of neuronal hyperexcitability, in carrageenan-inflamed and noninflamed rats (Drew et al. 2000) these effects were blocked by a CB1R antagonist. Spinal administration of anandamide produced CB1R-mediated effects in carrageenan-inflamed rats that were similar to that reported for HU210, but only inconsistent effects were observed in noninflamed rats (Harris et al. 2000). Upregulation of CB1Rs is also observed in the spinal cord following nerve injury, suggesting that regulation of spinal CB1Rs may contribute to the therapeutic efficacy of cannabinoids in neuropathic pain states (Lim et al. 2003). These data implicate involvement of spinal CB1Rs in both acute and persistent pain states.

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...

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...

Uses cardiac stimulant Crystodigin Lanoxin Digibind

Anatomically the nervous system is subdivided into the Central Nervous System (CNS), that which is encased in the cranial bone tissue and surrounded by the bone and cartilage, that is, the brain and spinal column, respectively. The function of the CNS is to control and integrate afferent and efferent signals. The network of neurons in the soft tissues of the bodies, impinging on organs and musculature is the Peripheral Nervous System (PNS). We will discuss the CNS in more detail later. For now, let us consider the PNS. PNS Peripheral Nervous System

Platinumcontaining cytotoxic drugs

In 21 patients with advanced non-small cell lung cancer carboplatin had no effect on the pharmacokinetics of paclitaxel 135-200 mg m2 as a 24-hour intravenous infusion (58). Peripheral neuropathy occurred in 13 of 37 patients treated with paclitaxel 175 mg m2 and carbopla-tin (59). The authors concluded that clinically important neurotoxicity increases with every cycle of chemotherapy. The peripheral neuropathy mainly affected sensory fibers without involving motor nerves. The same paclitaxel carboplatin chemotherapy in 28 women caused no signs of acute central neurotoxicity or neuropsychological deterioration however, 11 patients had a peripheral neuropathy (60).

Radiosensitizing Agents

Misonidazole and pimonidazole work, at least in vitro, by virtue of their high electron affinity. This induces the formation of free radicals and depletes radioprotective thiols, thereby sensitizing hypoxic cells to the cytotoxic effects of ionizing radiation. This allows single-strand breaks in DNA to occur, with subsequent inhibition of DNA synthesis followed by cell death. However, despite the promising in vitro results, the combination of misonidazole and radiation in several clinical trials (including a number of Phase III trials) since 1978 has failed to demonstrate improved survival. Furthermore, the clinical usefulness of misonidazole and a close analog (desmethylmisonidazole) was limited by severe but reversible toxicities, including nausea and vomiting and, more seriously, neurotoxicity (peripheral neuropathy).

James A Zackheim and Elizabeth D Abercrombie 1 Introduction

Acetylcholine (ACh) is a neurotransmitter widely distributed in the central nervous system (CNS) and peripheral nervous system (PNS). Its role as a neurotransmitter was first elucidated by Dale, who noted that ACh mimicked the effects of parasympathetic nerve stimulation and by Otto Loewi, who demonstrated the vagal release of a substance that slowed heart rate (1-3). More recently ACh in the CNS has been implicated in sensorimotor arousal, attention, sleep regulation, and learning and memory (4-8). Its distribution in the CNS includes the entire cortical mantle and hippocampus innervated by cholinergic neurons of the basal forebrain and the interpeduncular nucleus innervated by the medial habenula. The striatum, nucleus accumbens, and olfactory tubercle each contain cholinergic interneurons (9). The extraction of ACh from these areas in intact preparations historically has been largely via push-pull cannulae and now via microdialysis (10,11). Once extracted from the brain, however,...

Introduction 11 History

1.1.2 Drug Response and Toxicity Variability. It is an incontrovertible fact that large interpatient variability exists in response to medications. Variation in response has existed as long as medications have been used for the prevention and treatment of disease. In many ways, the field of pharmacogenomics began serendipitously in the 1950s after seminal observations describing variability in response to medications. Examples included peripheral neuropathy from isoniazid among slow acety-lators (2), prolonged apnea from succinylcho-line caused by pseudocholinesterase deficiency

Adverse effects profile of platinum compoundsgeneral aspects

Like carboplatin, oxaliplatin does not usually cause nephrotoxicity. In addition, both drugs are only moderately emetogenic, in contrast to cisplatin. The most important dose-limiting adverse effect of oxaliplatin is a sensory peripheral neuropathy, which has two different forms (i) a unique acute peripheral sensory (and motor) toxicity that often occurs during or within hours after drug infusion and which is rapidly reversible, and (ii) a peripheral sensory neuropathy related to the cumulative dose, which is generally moderate and slowly reversible, in contrast to the forms that have been described after cisplatin administration.

Increased Susceptibility To Salmonellosis Following Antagonism Of Substance Psubstance P Receptor Interactions In Vivo

The capsaicin-depletion study shown in Figure 1 could not identify the nature of the contribution made by the peripheral nervous system to this immune response. Therefore we focused our attention on substance P as a possible explanation for this observation. Mice were implanted with osmotic pumps which released a constant amount of a substance P antagonist, spantide II. Following oral challenge with Salmonella, groups of mice were monitored for the development of salmonellosis and for immune responsiveness. Mice receiving the substance P antagonist had increased salmonellosis and decreased survival when compared to mice receiving a control peptide13. Furthermore, spantide II treated mice had reduced IL-12 and interferon gamma responses to Salmonella than that seen in control groups. These results were not due to differences in the initial dissemination of Salmonella from the gut or due to global immune dysfunction induced by the substance P antagonist. Rather, these results...

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).

Organs and Systems Liver

In an open study of tizanidine for neuropathic pain, one patient developed abnormal liver function tests accompanied by nausea and vomiting, fatigue, confusion, weakness, and muscle aches (10). Within three weeks after withdrawal of tizanidine, the liver function tests returned to baseline and the symptoms resolved. Two other patients had transient asymptomatic rises in liver function tests, which returned to normal despite continuation of tizanidine. Transiently raised liver function tests during tizanidine treatment have occasionally been reported before (11-13).

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...

Gene Therapy for Angiogenesis

Therapeutic angiogenesis involves restocking angiogenic growth factors by administering recombinant proteins or endothelial growth factor gene. The recombinant proteins have severe limitation on its usage because it is expensive and difficult for large-scale production. On the other hand, gene therapy provides a systemic and long-term effect with modification in the effective dosage of the therapeutic agent. To evade potential problem of pathological angiogenesis, transient gene expression is usually preferred for this kind of treatment. Tsurumi et al. (51) introduced naked pDNA encoding vascular endothelial growth factor (VEGF) by intramuscular (IM) injection into ischemic hind limb muscles of a rabbit model and observed that the vessels and blood-capillaries were increased in rabbit muscles injected with VEGF compared with controls. An enhanced vascularity-induced perfusion followed by increased blood flow in the ischemic limbs was also observed. In clinical trial, Simovic et al....

Symptomatic Relief in Multiple Sclerosis and Spinal Cord Injury

A significant effect upon a subjective measure of spasticity was the principal finding in another large study of cannabis-based medicine in MS (Wade et al. 2004). The effects of a whole plant extract containing an equal proportion of THC and CBD (Sativex) was compared with placebo in a parallel-group, double-blind, randomised study in 160 MS patients. Eligible patients were experiencing one of the following symptoms which had proved refractory to standard treatment spasticity, muscle spasms, lower urinary tract symptoms, neuropathic pain or tremor. An oromucosal spray delivered 2.5 mg of each cannabinoid or matched placebo on each activation. After initial standardised dosing in an outpatient clinic, patients gradually titrated the dose upwards at home to a maximum of 48 sprays 24 h, aiming for an optimal balance between symptom relief and unwanted effects. Treatment period was 6 weeks, and the primary outcome measure was a composite derived from the VAS score of each patient's most...

Amitriptyline Elavil Laroxyl Triptyzol

- Neuropathic pain in adults - Neuropathic pain - Neuropathic pain continue several months after pain relief is obtained, then attempt to stop treatment. - In the treatment of neuropathic pain, amitriptyline is often combined with carbamazepine (except in pregnant women).

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...

What Is the Functional Role of Presynaptic Cannabinoid Receptors

It is evident from Sects. 4 and 5 that presynaptic CB1 receptors are ubiquitous in the central and peripheral nervous system. Even within one functional system, several components of the neuronal circuitry are equipped with CB1 receptors. This will be illustrated in two functional systems the extrapyramidal motor control system (Fig. 6) and the cerebellum (Fig. 7).

Combinations of Hypoxia Targeting Compounds and Radiation Activated Prodrugs with Ionizing Radiation

Diagram Egfr Under Hypoxic Conditions

Metromidazole and misonidazole (Fig. 5.3) are the prototype members of this class. They were administered to patients in the 1970s. Disappointingly, they showed very little efficacy sensitizing tumors but a high incidence of peripheral neuropathy (Urtasun et al. 1976 DiscHE et al. 1977). With the limited dose of misonidazole that can be administered to patients, almost all of the clinical trials of radiotherapy combined with misonidazole were negative (DiscHE 1985) however, a meta-analysis of 50 randomized trials later showed a small but significant benefit of misonidazole and other hypoxic radio-sensitizers when added to radiotherapy in head and neck cancers (OvErgaarD 1994).

Phenobarbital sodium Natrium5thyl5phenylbarbiturat

Neuropathy Peripheral Disorder and functional disturbance of the peripheral nerves. This may be manifest as numbness of the extremities, paraesthesia (pins and needles sensations), weakness of the limbs, or wasting of the muscles and loss of deep tendon reflexes. Peripheral neuropathy may be accompanied by disturbance of the autonomic nervous system, resulting in postural hypotension.Poor nutrition, particularly vitamin B deficiency, accompanying hazardous consumption of alcohol, is a common cause of peripheral neuropathy. Other drugs, including the opioids, may rarely cause this syndrome. Synonym Polyneuropathy.

Dorsal Column Visceral Pain Pathway

Visceral Pain Pathway

Schematic of neural pathways that process and modulate the transmission of information about nociceptive signals. In orange, the spinothalamic tract is shown, with signals originating in the peripheral nerve, crossing the midline, and ascending the anterolateral white matter of the spinal cord with many collateral outputs to the brainstem shown for the RVM and PAG. This tract terminates in the VPL VPM thalamus. In green, descending pain inhibitory pathways are shown, which connect the PAG to the RVM, and from there makes connections in the spinal cord. Other descending inhibitory pathways originating in the LC and noradrenergic nucleus A5 are also shown. In red, pathways that facilitate pain are shown originating in the RVM and descending to the spinal cord. Abbreviations A5, noradrenergic nucleus A5 D. Facil., descending facilitation pathway D. Inhib, descending inhibitory pathways DRG, dorsal root ganglion LC, locus coeruleus PAG, periaqueductal gray RVM, rostral...

Drugs Affecting Cholinergic Mechanisms

The nerve cell, or neuron, is an unusual looking cell (Fig. 8-1). A neuron may be only 0.1 mm in diameter but, may reach lengths of a meter or more. The threadlike extension from the cell body is the nerve fiber. These fibers interconnect in various special areas of the body, including the brain, the spinal cord, and the peripheral nerves. The function of the neuron is to transmit signals, or impulses. The dendrites specialize in receiving excitations, which may be from environmental stimuli (i.e., from peripheral parts of the body, or from another cell). The axon conducts the excitation away from the dendrite area (e.g., to the brain).1 This excitation, or impulse transmission, may be on a subconscious level. Transmissions of which the subject is not consciously aware are the type that control various body functions such as temperature, respiration, blood pressure, and peristaltic movements of the gastrointestinal tract. In addition to the traditional functions of a cell membrane,...

Alcoholic amblyopia See Amblyopia Alcoholic amnesia See Blackout

Alcoholic muscle disease See Myopathy. Alcoholic myelopathy See Myelopathy. Alcoholic myopathy See Myopathy Alcoholic neuritis See Peripheral neuropathy. Alcoholic neuropathy See Peripheral neuropathy. Alcoholic polyneuropathy See Peripheral neuropathy.

CH2CNH2 stimulatory activity

Phenylalkylamine Spirits

Amphetamines were covered in the section on the peripheral nervous system since they will have stimulation at adrenergic synapses leading to an increase in heart rate and dilation of the pupils. Their anorexic effects are both peripheral and central. The CNS effects include increased alertness, a delayed need for sleep (REM sleep is decreased), and euphoria. Because of their structural similarity to norepinephrine and dopamine, these compounds stimulate NE and Da production as well as prevent their reuptake. They may also inhibit monoamine oxidases. The principal sites of action seem to be the limbic system and the RAS.

Rimonabant and the Endocannabinoid System

Dogrul et al. (16) reported that diabetic neuropathic pain is common and is resistant to morphine treatment. Streptozotocin (200 mg kg) was used to induce diabetes in mice, which were tested between 45 and 60 days after onset of diabetes. Antinociception Ibrahim et al. (17) tested the effects of AM 1241 (a selective CB2 receptor agonist) on experimental neuropathic pain in rats. Tactile hypersensitivity and thermal hypersensitivity were induced by ligation of L5 and L6 spinal nerves. AM 1241 dose-dependently reversed hypersensitivity. When tested in CB1 knockout mice using the same ligation procedure, AM 1241 was effective in reducing pain sensitivity, suggesting that this peripherally active agonist blocks neuropathic pain. The authors suggest that CB2 receptor agonists, devoid of CNS activity, are predicted to be effective without the CNS side effects of centrally acting cannabinoid agonists.

Endocannabinoids in the modulation of pain

Thermal hyperalgesia, an effect reversed by rimonabant (Richardson, Kilo et al., 1998). Interestingly, selective activation of cannabinoid CB2 receptors suppresses hyperalgesia evoked by intradermal capsaicin (Hohmann et al., 2002). Similarly, it was demonstrated that AM1241, a selective CB2 receptor agonist, dose dependently reversed tactile and thermal hypersensitivity produced by ligation of the L5 and L6 spinal nerves in rats (Ibrahim et al., 2003). These effects were antagonized by CB2, but not CBj, receptor antagonists AM1241 was also effective in CBj KO mice, suggesting the potential utility of selective CB2 receptor agonists for neuropathy (Ibrahim et al., 2003). Pain inhibition by activation of CB2 receptors that are not present in the brain is an attractive approach, as CB2 receptor agonists are not likely to produce the euphoria and high associated with marijuana smoking or the use of synthetic cannabinoids that activate the CBj receptors. It has been suggested that whereas...

Medical And Behavioral Toxicity Overview

The main adverse neural consequences of chronic alcohol consumption are the following brain damage (manifested by dementia and alcohol amnestic syndrome) complications of the withdrawal syndrome (seizures, hallucinations) and peripheral neuropathy. Chronic alcohol consumption results Milder forms of these disorders are also detectable with neuropsychologic testing or brain imaging techniques (computed tomography CT scans magnetic resonance imaging MRI ). Studies of detoxified alcoholics (without other evidence of organic brain damage) reveal that 50 to 70 percent have impairments in neuropsychologic assessment (Eckardt & Martin, 1986). In most of these cases there is reversibility with abstinence from alcohol. Severe liver disease (e.g., acute hepatitis, advanced cirrhosis) may also contribute to this neurologic impairment. CT scans reveal that many alcoholics have cerebral atrophy, which consists of decreased brain weight, an increase in spaces (sulci) between various regions of...

Stimulants Relaxants Weight Control and Pain

Nervous System Spinal Cord

Amphetamine works by manipulating the levels of certain neurotransmitters in the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS is made up of the brain and spinal cord, whereas the PNS includes all the nerves in the rest of the body (including muscle nerves Figure 5.3). As has already been discussed, the CNS and PNS are made up of billions of nerve cells. When amphetamine is taken, it enters these nerve cells and displaces the Figure 5.3 The central and peripheral nervous systems consist of the brain, spinal cord, and peripheral nerves that extend to the rest of the body. Drugs such as amphetamine manipulate the release of chemical signals in the brain, which in turn sends signals down the spinal cord and throughout the body. Many drugs such as caffeine and amphetamine do not cause the production or release of additional chemicals but act to block the reabsorption of chemicals, such as dopamine, which results in higher concentrations of these chemicals...

Use Of Endocannabinoidbased Substances In Animal Models Of Disorders

And neuropathic pain occurring in humans. Several animal models of these types of pain have been developed, and in many but not all instances cannabinoid receptor (both CBj and CB2) agonists and antagonists have been found to exert antihyperalgesic or hyperalgesic activity, respectively (for a review, see Walker and Huang, 2002). However, in no case were inhibitors of endocannabinoid inactivation tested, which would have provided further evidence for the postulated endocannabinoid tone controlling chronic and inflammatory pain. Instead, an important study recently revealed how the endocannabinoid system plays a major role in the phenomenon known as stress-induced analgesia. According to this study, animals submitted to a short period of stress, such as a non-noxious electrical shock, become hypoalgesic to stronger nociceptive stimuli, partly because of the activation of the endogenous opioid system. Using such a model, it was shown that endocannabinoids and CBj receptors mediate...

Cannabinoids and Analgesia

5ht Immuno Spinal Cord

Pain pathways are described at three levels in the periphery, where it originates at the level of the spinal cord, where some control gating the transmission of pain exists and in the CNS, particularly at the level of the periaqueductal gray. CBj receptors are found on peripheral nerves (59), and injection of anandamide into tissues swollen from carageenan-induced inflammation has been shown to reduce pain in rats (60). But there is much more evidence for a spinal and a central site of action of cannabinoids. To understand better some of the sites and mechanisms of action of cannabinoids, a simplified pain pathway model is presented in Figs. j0 and jj.

Polydrug use abuse See Multiple drug use

Polygesic Drug containing more than one substance under international control Dexam-fetamine sulfate and Pentobarbital. Polymarcol Phenobarbital. Polyneuritis See Polyneuropathy. Polyneuropathy 1. A disease process involving a number of peripheral nerves (literal sense). 2. A non traumatic generalized disorder of peripheral nerves, affecting the distal fibers most severely with proximal shading (i.e., feet, before, or more severe, than hands), and typically symmetrical most often affects motor and sensory fibers almost equally, but can involve either one solely or very disproportionately classified as axon degenerating (atonal), or demyelinating many causes, particularly metabolic and toxic familial or sporadic in nature. An average of 10 percent of heavy alcohol users show signs of polyneuro-pathy.

The development of Sativex a natural cannabisbased medicine

Capitate Stalked Trichomes

GW entered into its pivotal phase III clinical trials programme in March 2001. The initial phase III studies involved patients with multiple sclerosis (MS), neuropathic pain and cancer pain. The results of the first four phase III studies were reported in November 2002, and six of the trials have now been completed, yielding positive results, and a further three are due to report in 2005.

Respiratory effects of inhaled cannabis vapor andor smoke

Cannabis Respiratory Effect

MS Multiple Sclerosis is characterized by increasing neuropathic pain and degenerative loss of muscle control in two forms involuntary movements (spasms) and the inability to move (ataxia). Cannabis helps improve movement affected by each of these, while reducing or stopping the pain and related depression.

Brachial plexus anesthesia

In unpremedicated patients who underwent supraclavicular brachial plexus block for upper limb surgery, blocks were performed using a peripheral nerve stimulator and 0.5 ml kg of bupivacaine 0.375 (1c). Spiro-metric and ultrasonographic assessments of diaphragmatic function were made at intervals. Of 30 patients, 15 had complete paralysis of the hemidiaphragm, five had reduced diaphragmatic movement, and 10 had no change. Those with complete paralysis all had significant reductions in pulmonary function and those with reduced or normal movement had minimal changes. Only one of the patients had respiratory symptoms and the oxygen saturation remained unchanged. This may not be the case, however, in patients with significant pre-existing respiratory disease or in obese people the authors therefore suggested caution in choosing this approach as a safer alternative to general anesthesia in such individuals.

Fluoxetine Sertraline Paroxetine Citalopram Fluvoxamine

Drug Sertraline Mechanism Action

Little knowledge of psychology, and the prescriptions are often for behaviors not related to mood, such as kleptomania, weight gain, or neuropathic pain. Is Prozac truly a panacea for such a wide scope of problems and populations Or is the hype of Prozac over-reaching its powers This chapter will attempt to pull the curtain away from Prozac mythology with a discussion of SSRI benefits and drawbacks.

Brain Gut Peptides CCK Neuropeptide Y Galanin

Neuropeptide Y (NPY) is an amidated 36 amino acid peptide with a wide distribution in the central and peripheral nervous system. NPY is highly concentrated in the hippocampus and the amygdala.80 Cholinergic interactions of NPY in the neocortex have been reported.99 Of particular interest are the findings on the potential influence of NPY transmission in memory and cognition. Post-training i.c.v. administration of NPY to mice resulted in improved retention, when mice were retested 7 days later.80 When testing the performance of mice in a T-maze active avoidance task, i.c.v. administered NPY had no effect on acquisition but improved retention. Peripheral administration had no effect. The effect of NPY on memory retention was time-dependent. When NPY was administered immediately prior to the retention test, enhanced recall was observed. As NPY did not alter acquisition, this enhanced recall most probably reflects enhanced retrieval of previously stored memories. NPY was found to reverse...

Cannabinoid Receptor Activation Of Ion Channels

Cannabinoid receptors are located on the pre- and post-synaptic regions of multiple types of neurons (Herkenham et al., 1991 Tsou et al., 1998). If cannabinoids inhibit calcium channel currents pre-synaptically then transmitter release could be inhibited. Indeed it has recently been demonstrated that inhibition of N- and Q-type calcium channels by CBX receptor activation reduces the probability that neurotransmitter will be released in response to an action potential in hippocam-pal pyramidal neurons (Sullivan, 1999). Pre-synaptic inhibition of calcium channels provides a mechanism for studies that have shown cannabinoids to inhibit acetyl-choline, noradrenaline, glutamate, and GABA release in hippocampal neurons (Gifford and Ashby, 1996 Shen et al., 1996 Gessa et al., 1997 Kathmann et al., 1999 Katona et al., 1999), noradrenaline release at sympathetic nerve terminals (Ishac et al., 1996), and NMDA stimulated dopamine release in the striatum (Kathmann et al., 1999). In the peripheral...

Theophyllinthylamphetamine Fenetylline

Thiabital Drug containing more than one substance whereof one under international control Phenobarbital. Thiambuten Diethylthiambutene. Thiamine deficiency syndrome The classic thiamine deficiency syndrome (E51) is beriberi, rarely seen except in areas where polished white rice is the dietary staple. In most societies, however, thiamine deficiency is largely associated with excessive alcohol use. One manifestation is Wernicke encephalopathy (E51.2) another is peripheral neuropathy, and the two may occur together. Thianal Phenobarbital. Thiaphen Phenobarbital. Thienylphencyclidine Tenocyclidine. Thing 1. Colloquial term for heroin. 2. Colloquial term for cocaine. 3. Colloquial term for the main drug interest at the moment. Things 1. Colloquial term for heroin. 2. Colloquial term for cocaine. 3. Colloquial term for joint of marijuana. Thinner Solvent used for inhaling. Thinner sniffing Colloquial term for inhaling of solvents.

Outlook Src As A Target For Other Indications More Selective And Dual Src Inhibitors

Apart from a few isolated studies, the potential of Src inhibitors for inhibition of different tumors has not yet been extensively examined. A lack of enthusiasm in this area is certainly caused by a lack of convincing epidemiological studies implicating Src in the etiology of human tumors. Our preliminary studies with HT29 colon cancer xenografts in nude mice were not very encouraging (Fig. 5). However, recent in vitro data on potent effects of Src pyrrolopyrimidine inhibitors on prostate cell migration and invasion would warrant examination of existing compounds in suitable in vivo cancer metastases models. In accord with this notion, the Src inhibitors PP1 and herbimycin A have been shown to suppress collagen type I III-dependent decrease in cadherin E, coupled to changes in cell-cell adhesion, proliferation, and migration of pancreatic carcinoma cells (25). In another tumor type, malignant peripheral nerve sheath tumors, there is a correlation between Src activity, inhibition by a...

General adverse reactions

In a survey of more than 2000 patients treated with iso-niazid, the most frequent adverse effects were rash (2 ), fever (1.2 ), jaundice (0.6 ), and peripheral neuropathy (0.2 ). Seizures can also occur. Isoniazid prolongs the half-life of rifampicin and other drugs metabolized by the liver. Morbilliform, maculopapular, purpuric, and urticarial rashes, with or without fever, are considered to be of allergic origin. Hematological adverse effects consist of agranulocytosis, thrombocytopenia, pure red cell aplasia, and eosinophilia (SEDA-9, 268). Dyspnea, with thoracic pain, cough, fever, and eosinophilia, as well as micronodular densities in the chest X-ray, may also be due to an immunological process (1). Vasculitis associated with antinuclear antibodies has been observed, as well as arthritic symptoms (2). Liver injury (mainly hepatocellular) has been considered another form of hypersensitivity reaction, but usually occurs during combined antituberculosis treatment with rifampicin in...

Classical Herbal Drugs of Abuse 1931 Cannabis and Tetrahydrocannabinol

The cannabinoids are ligands of the cannabinoid G-protein coupled receptors. Evidence for the existence of a human cannabinoid receptor was found in the mid-1980s, and the CBi receptor was confirmed by cloning in 1990. A second cannabinoid receptor, the CB2 receptor, was confirmed by cloning in 1993 10 . The CB1 receptor is predominantly found at central and peripheral nerve terminals, whereas the CB2 receptor is mainly distributed in immune cells 9 .

The Nervous System

The nervous system is a complex part of the human body concerned with the regulation and coordination of body activities such as movement, digestion of food, sleep, and elimination of waste products. The nervous system has two main divisions the central nervous system (CNS) and the peripheral nervous system (PNS). Figure 22-1 illustrates the divisions of the nervous system.

Carbamazepine

The USA in 1974 (approved for children over 6 years of age in 1979). Along with phenytoin, carbamazepine is one of the most widely used anticonvulsant drugs. It is also often used in combination therapy with tricyclic antidepressant drugs and can be used in the treatment of neuropathic pain. Like many other anticonvulsant drugs, the pharmacodynamic effects of carbamazepine are better correlated with serum or plasma concentrations rather than drug dosage. The proposed mechanism of action for carbamazepine is that of stabilizing the inactive state of voltage-gated sodium channels in the brain. The result is that brain cells are less excitable, and seizure activity is reduced. Side effects from drug levels exceeding the optimum therapeutic level include loss of coordination, drowsiness, and arrhythmia.

Arachidonoylglycerol

2-AG was also detected in the peripheral nervous system. Huang et al. (1999) reported that 2-AG is present in the rat sciatic nerve, lumbar spinal cord, and lumbar dorsal root ganglion, and Di Marzo, Breivogel, et al. (2000) demonstrated the occurrence of 2-AG in the mouse spinal cord. 2-AG has also been shown to occur in the rat retina and bovine retina (Straiker et al., 1999 Bisogno, Delton-Vandenbroucke, et al., 1999). Several tumors of nervous system origin have also been shown to contain 2-AG Maccarrone, Attina, Cartoni, et al. (2001) reported that 2-AG was detected in the tumoral human brain (meningioma) and human neuroblastoma CHP100 cells.

Gabapentin

Available human and experimental data do not indicate a substantial teratogenic risk of gabapentin monotherapy. However, definite risk assessment is not possible due to a lack of experience. There is no reason to terminate a pregnancy which has occurred during treatment. As is the case with other anticonvulsants, especially with combination therapies, an increased rate of birth defects is to be expected. An expanded prenatal diagnosis with a detailed fetal ultrasound during the second trimester should be performed to rule out major disturbances of structural development. Gabapentin should not be used for treatment of non-epileptic diseases (neuropathic pain, psychiatric diseases) when pregnancy cannot be ruled out.

Drug additives

The addition of fentanyl 1 mg ml to ropivacaine 7.5 mg ml did not improve nerve blockade by axillary brachial plexus anesthesia in a double-blind, randomized study in 30 patients undergoing orthopedic procedures (31). In another double-blind, randomized study, 60 patients receiving axillary brachial plexus blockade were given 0.25 bupivacaine 40 mg, 0.25 bupivacaine 40 mg plus fentanyl 2.5 mg ml, or 0.125 bupivacaine 40 mg plus fentanyl 2.5 mg ml (32). The addition of fentanyl 2.5 mg ml prolonged sensory and motor blockade without any improvement in the onset of anesthesia and no significant increase in adverse effects. These two studies have reaffirmed the current position of conflicting results in studies of the benefits of adding fentanyl to local anesthetics for peripheral nerve blockade.

Conclusions

The complex pharmacology of cannabinoids, whether exogenous or endogenous, exists only in its infancy. From the discovery of specific cannabinoid receptors and other targets to that of endogenous ligands and a biochemical pathway of synthesis, degradation and reuptake, the therapeutic potential of cannabinoids is only emerging. Central actions on motor regulatory pathway may give rise to drugs useful in dyskinesias such as Huntington's or Parkinson's disease. Central effects on glutamate release may yield medications aimed at decreasing the pathological consequences of strokes. The analgesic effects of cannabinoids already see some application in neuropathic pain (104). Could an antagonist help in increasing memory in Alzheimer's disease patients Already, central effects such as appetite stimulation and antiemetic properties are clinically used. Peripheral effects on the cardiovascular system could help in the development of novel antihypertensive medications. The peripheral...

Nitrofurantoin

Nitrofurantoin administration may result in nausea, vomiting, anorexia, rash, peripheral neuropathy, headache, brown discoloration of the urine, and hyper-sensitivity reactions, which may range from mild to severe. Acute and chronic pulmonary reactions also have been seen.

Functional Roles

Response to a noxious stimulus and hence contribute to the transmission of pain. While AMPA receptors are activated in response to brief acute stimuli and are involved in the fast events of pain transmission, NMDA receptors are only activated following repetitive noxious inputs, under conditions where the stimulus is maintained (for more details see Chapter 21). NMDA receptors have been implicated in the spinal events underlying 'wind-up', whereby the responses of dorsal horn neurons are significantly increased after repetitive C-fibre stimulation despite the constant input. Thus the activation of this class of receptors brings about a marked increase in neuronal excitability and is responsible for the amplification and prolongation of neuronal responses in the spinal cord. Substantial evidence exists for the involvement of NMDA receptors in various pathological pain states. Studies have demonstrated the effectiveness of NMDA receptor antagonists in animal models of inflammation,...

Drug studies

In a double-blind, placebo-controlled study of the use of intravenous lidocaine for neuropathic pain, 16 patients were given 5 ml kg intravenously over 30 minutes (10). Lidocaine was better than placebo in relieving pain. The major adverse effect was light-headedness, which occurred in seven patients given lidocaine and none given saline. Other adverse effects included somnolence, nausea and vomiting, dysarthria or garbled speech,

Antidepressants

Surprisingly, antidepressants are also effective in reducing neuropathic pain. We do not know precisely how antidepres-sants accomplish this, but scientists believe that the increased levels of norepinephrine and or serotonin outside the nerve cells somehow dampen pain signals that enter the brain from the spinal cord. TCAs appear to be the most effective antidepressants in relieving the symptoms of neuropathic pain. Listed below are some commonly prescribed TCAs with their brand names in parentheses Amitriptyline is usually the treatment of choice for neuropathic pain. Some selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac ), paroxetine (Paxil ), sertraline (Zoloft ), and clomipramine (Anafranil ) can be used, but they don't appear to be as effective as TCAs. The doses for TCAs in treating neuropathic pain are usually lower than those for treating depression, and the drugs usually start to take effect more quickly in relieving pain than they do in relieving...

Nociceptors

Mechanical, heat, and chemical stimuli. Primary afferents have a unique morphology. The cell bodies, which are found in the dorsal root ganglion, lack dendrites and synapses and are encased in satellite cells that insulate them. The axon bifurcates, sending a branch to the spinal cord and branch to the periphery. Hence, the sensory apparatus is found on an axon terminal, and indeed action potentials in the peripheral nerve lead to secretion of neurotransmitter at both the peripheral and central terminals. The biochemical machinery of nociceptors includes a variety of molecular transduction elements such as transient receptor potential (TRP) channels, acid sensing channels, and P2X3 receptors, as well as particular neurotransmitters including glutamate, substance P, and calcitonin gene-related peptide (CGRP). On the central terminals are found presynaptic receptors that modulate neurotransmitter release.

CB2Like Receptors

It is possible that palmitoylethanolamide may produce antinociception in rat and mouse models of inflammatory or neuropathic pain by acting on a CB2-like receptor (Calignano et al. 1998, 2001 Conti et al. 2002 Farquhar-Smith et al. 2002 Farquhar-Smith and Rice 2001 Helyes et al. 2003). The existence of such a receptor is supported by the finding that even though palmitoylethanolamide lacks significant CB2 receptor affinity or efficacy (Griffin et al. 2000 Lambert et al. 1999

Endocannabinoids

In 1992 the first endocannabinoid, anandamide (V-arachidonoylethanolamine), which is the ethanolamide of arachidonic acid, was isolated from the porcine brain (Devane et al., 1992). It was shown both to occupy cannabinoid receptors and to mimic the functional effects of A9-tetrahydrocannabinol. Anandamide is the prototype of a family of V-acylethanolamines and other polyunsaturated V-acylethanolamines (Hanus et al., 1993), which have similar effects via activation of G protein-linked cannabinoid (CBX or CB2) receptors. To date, CBX receptors have been found predominantly in the brain and peripheral nervous system, and the CB2 receptors appear to be exclusive to immune tissues.

Nedaplatin

Nedaplatin (CDGP, 254-S, cis-diamminegly-colatoplatinum) has some structural similarities to cisplatin and carboplatin. Since 1995 it has been available for therapeutic use in Japan. In phase II trials it had promising antineoplas-tic activity in patients with head and neck cancers, NSCLC, esophageal cancer, testicular tumors, and cervical cancer. A distinct number of patients with ovarian cancer have responded to nedaplatin (e.g. 100 mg m2 intravenously) even after relapsing following treatment with cis-platin carboplatin and cyclophosphamide. Its pharmacokinetic behavior is similar to that of carboplatin. It causes less nephrotoxicity than cisplatin, but hematological toxicity is dose-limiting. Other adverse effects include nausea vomiting and mild peripheral neuropathy (12r, 13r, 34r). Although nedaplatin is less nephrotoxic than cisplatin, incidental cases of severe nephrotoxicity have occurred. In addition, ototoxicity, similar to that observed after cisplatin, has been...

Tetraplatin

The further development of the third-generation platinum derivative tetraplatin (ormaplatin, trans-d,l-1,2-diaminocyclohexane tetrachloro-platinum) has been abandoned, because drug-induced severe motor and sensory peripheral neuropathy occurred even at low cumulative doses. The high neurotoxic potential of tetraplatin may be associated with its pharmacokinetics it is rapidly metabolized to 1,2-DACH-platinum dichloride, which was 3.8 times more neurotoxic than oxaliplatin in a neu-rite outgrowth assay (43e).

Sibutramine

This weight control medicine appears to work by making people feel more full while eating a meal, thereby reducing appetite. People using sibu-tramine eat less regardless of whether they are trying to lose weight. In rats the drug increases the rate at which the body consumes stored energy, burning off calories. A similar action has been measured in humans. Sibutramine has also been used for treating nerve pain caused by diabetes. One research study found that the drug improved attention and muscular coordination.

Local Anesthetics

Peripheral nerve block anesthesia involves injecting the drug near the nerves close to the area to be anesthetized. Epidural anesthesia results when the local anesthetic is injected into the epidural space between a lumbar and sacral vertebra. Several drugs can safely produce useful levels of anesthesia for obstetrics as well as postoperative pain. Another method of utilizing local anesthetics is to inject solutions into subarachnoid spaces (e.g., the spaces between certain vertebrae).

Behaviour And Pain

Pain we can start to see links between state of mind and the level of pain experienced. This may be just one early step in the understanding of some of the chemistry of the psychological aspects of pain. Independently of their effects on mood, antidepressants increase activity in these descending control systems and are used as analgesics in neuropathic pain states. Individual differences in levels of pain, in the transition from acute to chronic pain, in susceptibility to neuropathic pain after nerve damage and in analgesic effectiveness may have a genetic basis. There is marked variability in animal genetic strains in terms of the sequelae of tissue and nerve damage and even in their responses to morphine. Given the huge range of human phenotypes, this may indicate important individual differences in susceptibility to pain and analgesia but we have no way of monitoring this possibility.

Aminoalkylindoles

Alkyloxy Indole

AM1241 (40, Fig. 10), a highly CB2-selective and potent agonist (Ibrahim et al. 2003 Malan et al. 2001) was recently developed by Makriyannis. Design of this molecule incorporated the N-methylpiperidinyl-2-methyl substituent at the N-1 position and a novel 2-iodo-5-nitrobenzoyl group at C-3. AM1241 exhibits remarkably high peripheral analgesia in vivo and does not produce catalepsy, hypothermia, inhibition of spontaneous locomotor activity, or impairment of performance on the rotarod apparatus. The potential use of this CB2 receptor agonist for the treatment of neuropathic pain is being explored.

Anergia Anergy

Ennese surgeon, Carl Koller, acting on the suggestion of Sigmund Freud. A solution of the drug was applied directly to the part to be operated on. Soon it was being injected under the skin to facilitate small, local operations, and it was later successfully used for larger procedures by injecting it into the trunks of nerves supplying a part. Now, synthetic cocaine substitutes are widely used. Major operations on the lower half of the body can be carried out after injecting a suitable local anesthetic into the fluid-filled space between the spinal cord and its outer membrane coverings (spinal anesthesia). Painless childbirth can be achieved by an epidural block, which involves injecting the anesthetic agent through a fine tube threaded into the space surrounding the tough membrane covering the lower end of the spinal cord, thus dulling the emerging nerves that supply the pelvic organs. In recent years much interest has been shown in acupuncture anesthesia, whereby apparently painless...

Inositol And Ip6

Effects Inositol acts as a cell membrane stabilizer. It also helps redistribute body fat, keep cholesterol low, prevent eczema, and keep hair healthy. Claims that myoinositol lowers triglycerides and cholesterol in the blood, protects against cardiovascular disease, promotes sleep, or relieves anxiety are, as yet, unproven, though these last two effects may result from its effects on phosphatidylinositol levels in brain cells. It has been shown to provide some benefit in improving sensory nerve function in those with diabetic peripheral neuropathy, though more research is needed to determine its exact role in this disease.

The Powers Of Peyote

Mind altering drugs throughout the world (Phontastica, 1924), obtained some peyote extract from the Parke-Davis Pharmaceutical Labs of Detroit in the 1880s, His studies laid the gixxnKlwoik for the isolation of mescaline in 1896 by Arthur Heffler. Mescaline (3,4,5-trimethoxy-phenylethylamine) is not an indole like the majority of psychedelics, but is structurally related to the adrenal hormones and to the synthetic stimulant methamphetamine, which arc all very active in the peripheral nervous system. It may be that mescaline does convert to an iixJole structure once it's in the body. The nausea-pi woking qualiiy of peyote is gieatly reduced, if iK)t entirely eliminated, when synthetic mescaline is used.

Acitretin

Nervous system The possible negative effects of short-term oral acitretin 1 mg kg day on peripheral nerve function have been assessed in a small prospective study in 13 patients (69c). Patients with conditions related to peripheral neuropathy were excluded. There was a fall in the mean amplitude of the sensory action potential of the superficial peroneal nerve after 1 and 3 months of therapy. There was a significant change in one or more neurophysiological parameters in three of 13 patients after 1 month

Anorectic Class

The first diet drug to receive scientific endorsement was thyroid hormone. Its use for this purpose began in the 1890s on the theory that it would boost a person's metabolism and thereby promote faster use of calories. The same theory made dinitrophenol a standard diet drug before World War II. Although it boosted metabolic rate, it also boosted rates of cataracts and of harm to the peripheral nervous system (which involves the functioning of various organs and muscles). For those reasons the drug was abandoned. In the 1930s amphetamines became available and quickly became a popular diet aid despite their potential for abuse.

Myotonolytics

Among the myotonolytics, in the broadest sense, there are very different agents, such as baclofen, carisoprodol, quinine ethyl carbon-ate, chlormezanone, Clostridium botulinum toxin, dantrolene, fenyramidol, mephenesin, methocarbamol, orphenadrine, pridinol, tetrazepam, tizanidine, and tolperisone. For antiepileptics used for the treatment of neuropathic pain, see Chapter 4.8.

N 168 r 0919

Clinical trials are evaluating the efficacy of THC, cannabidiol, and other cannab-inoids in the treatment of nausea after cancer chemotherapy, appetite loss, multiple sclerosis, and neuropathic pain (16). A common clinical question might be How will monitoring plasma cannabinoid concentrations aid clinical management of these patients As with any new pharmaceutical preparation, it is necessary to study the drug's pharmacokinetics to more clearly understand required doses, frequency of dosing, contributions of metabolites to effects or toxicity, elimination profiles, and metabolism and excretion in different populations, including newborns, children, ethnic groups, diseased individuals, and the elderly. For example, one must determine the median effective dose, ED50, for these populations to assist clinicians who must prescribe doses that will be efficacious but avoid toxicity.

Gabab receptors

GABAB receptors are found in both the peripheral nervous system and CNS. They were first identified in the late 1970s, during studies of noradrenaline release from axon terminals of sympathetic post-ganglionic fibres in rat atria. GABA was found to reduce the evoked release of transmitter but this action was not blocked by the conventional antagonists bicuculline and picrotoxin. The effect of GABA was mimicked not by muscimol but by the compound ( )-4-amino-3-(4-chlorophenyl)butanoic acid (baclofen), a GABA analogue that has no effect on GABA receptors linked to Cl channels. To distinguish between the established receptors and the newly identified bicuculline-insensitive receptors the terms GABAA and GABAB were introduced (reviewed in Bowery 1993).

Stavudine

A five-fold increase in the risk of distal sensory neuropathy has been reported in patients taking stavudine plus isoniazid (55 versus 11 ) compared with patients taking stavudine without isoniazid (59). In nine of 12 patients, the neuropathy resolved on changing antiretroviral drugs. Peripheral neuropathy is a distressing complication during treatment with stavudine and the risk is considerably increased with co-administration of isoniazid. This combination of drugs should be avoided, if possible, in patients with tuberculosis and AIDS.

Immediate Early Genes

Immediate Early Genes Iegs

In addition to classical IEGs such as krox 24 being involved in memory and LTP, we have recently discovered that transcription factors normally associated more with stress responses are also activated by LTP-inducing stimulation. In particular, we have been interested in how transcription factors such as Activating Transcription Factor 3 (ATF3) might be involved in LTP and hence memory processes. This interest stems in part from studies showing that c-Jun N-terminal kinase (JNK) activity, which is associated with some forms of cellular stress and apoptosis (see refs. 44 and 63, as well as 62), is also activated in the CNS by environmental stimulation.65 Furthermore, one JNK target, c-Jun, is switched on in neurons during LTP5 ATF3 (also called LRF-1 in rat, LRG-21, CRG-5 and TI-241 in mouse) is a member of the ATF CREB family of bZIP transcription factors but cannot be detected basally in neurons.21,22,30,32,35 ATF3 has the characteristics of an IEG, with its induction being...

Subtypes

Nicotinic acetylcholine receptors are ligand-gated ion channels. This receptor is composed of five polypeptide subunits that form a barrel-like structure around a central ion channel.21 In contrast to nAChRs located in the periphery which are composed of al, (31, 6, e, Y subunits, the standard configuration of the neuronal nAChRs include combinations of a and ( sub-units. However, a7, a8, and a9 subunits can also form functional nAChRs that consist of a single subunit type.25 Presently, the subunits a2-a7 and (2-(4 have been identified in the human brain and the distribution of these subunits in the human brain are presently being examined (see ref. 71 for a review of the nAChRs in the human brain). As in other receptor systems, much more work has examined the distribution of nAChR subunits in the rodent brain. In rodent models, the a3, a7, (2 subunits, and to a lesser extent the a4 subunit are expressed in the hippocampus (see ref. 73). The a2, a4, a5, a7, (2, and (4 subunits have...

Fossil Fuel

Toxicology Hexanes can cause peripheral nerve damage. Toluene can affect the central nervous system. Butane and cfcs do not seem to cause neurological damage, but butane can trigger cardiac arrest. Chloro hydro carbons are toxic to the liver. Gasoline contains hexanes, benzene, other hydrocarbons, triorthocresyl phosphate, and sometimes lead, all of which are toxic. Benzene is carcinogenic. The neurotoxin is the metabolite 2,5-hexanedione (HD). Hexane seems as if it should be pretty innocuous stuff it's just a straight hydrocarbon chain but like MBK it metabolizes into 2,5-HD in the body, which causes peripheral neuropathy. The neuropathy begins to develop several months after continued exposure, begins painlessly, and may continue to develop for several months after cessation of exposure. Chronic inhalation of toluene may produce cognitive dysfunction, hearing loss, equilibrium disorder, and damage to the optic nerve. There is no convincing evidence that pure toluene produces...

Yohimbine

GENERAL Preparations Brand name Yocon only. Class Aphrodisiac. Used in Medication-induced sexual dysfunction. Mechanism of action Unknown effects in the brain. In the peripheral nervous system, it changes the muscle tone of blood vessels, resulting in enhanced blood flow to the genitals during sexual activity.

Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

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