Peripheral Events In The Initiation Of Pain

SENSORY RECEPTORS

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 first stage in the transmission of acute pain involves activation of specialised sensory receptors, the nociceptors, on peripheral C-fibres. These receptors include mechano-, chemo- and thermoreceptors. The terminology of'receptor' for transmission of somatosensory information can incorporate the type of nerve fibre they are activating, the proposed transduction mechanisms, as well as the form of the adequate stimulus which activates them. Generally, the nerve fibres which respond to non-painful, low-threshold stimulation are the Aft-fibres and their associated endings. By contrast, A^-fibres can be nociceptive or non-nociceptive while nociceptors associated with C-fibres are often termed polymodal since they can respond to a variety of adequate stimuli. The transduction mechanism associated with the free endings of these latter fibres has still to be ascertained. Some C-fibres can, however, also convey low-threshold information while some A^-fibres have also been shown to behave as polymodal receptors in their own right with A£-mechanoreceptors behaving like C-polymodal afferents after sensitisation.

Primary afferent fibres mediating painful inputs

The somatosensory primary afferent fibre, which conveys sensory information to the spinal cord, can be classified into several classes, according to the transduction

Table 21.1 Classification of somatosensory primary afferent fibres innervating the skin

Primary afferent fibre type

Mean diameter

Om)

Myelination

Mean conduction velocity (m/s)

6-12

Myelinated

25-70

AS

6-5

Thin myelinated

10-30

C

0.2-1.5

None

<2.5

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 afferent fibres differ in their conduction velocity and degree of myelination, and can be distinguished by their diameter. The large diameter AyS-fibres are myelinated by Schwann cells and hence have a fast conduction velocity. This group of nerve fibres innervates receptors in the dermis and is involved in the transmission of low-threshold, non-noxious information, such as touch. The A^-fibre is less densely myelinated and conveys both non-noxious and noxious sensory information. The unmyelinated C-fibre conveys high-threshold noxious inputs and has the slowest conduction velocity of all three fibre types.

A^-fibres

The large diameter AyS-afferent fibre enters the dorsal horn of the spinal cord through the medial division of the dorsal root. It then descends through the medial region of lamina I or II, or alternatively, curves around the medial (central) edge of the dorsal horn down to the ventral horn. On reaching deeper laminae, laminae IV and V, the AyS-fibres ascend back up into laminae III and IV where they repeatedly subdivide and form a characteristic termination pattern. The densest arborisation appears to occur in lamina III. Axons originating from specialised muscle stretch receptors have collaterals that pass ventrally to make monosynaptic connections with neurons of laminae V, VI and VII. Some also extend to laminae VIII and IX of the ventral horn where they synapse directly onto motor neurons and form the basis of monosynaptic reflexes.

A^-fibres

The termination pattern exhibited by A^-fibres is entirely different from that of large AyS-fibres. A^-fibres travel extensively in Lissauer's tract, overlying the dorsal horn and their terminals form a plexus at the surface of the spinal cord A^-fibres from high-threshold mechanoreceptors distributed to laminae I, II outer and V. Projections also appear to terminate on the contralateral side, in lamina V. A^-fibre innervations from deep tissues (muscles and joint) have been shown to terminate exclusively in lamina I, or in laminae IV and V.

C-fibres

Extensive studies have investigated the organisation and termination patterns of C-fibres, employing various techniques including Golgi staining, degeneration techniques and HRP transport. Unmyelinated C-fibres enter the spinal cord through the lateral part of the dorsal white matter, including Lissauer's tract. Studies have shown that unmyelinated primary afferents terminate in the superficial dorsal horn, although there is conflicting evidence as to whether the terminations are restricted to lamina II or whether it includes both laminae I and II. Current evidence suggests that lamina II is the main termination area for cutaneous primary afferent C-fibres while that for fibres is in lamina I.

TISSUE DAMAGE AND CHEMICAL MEDIATORS

These polymodal receptors, on C-fibres, can be selectively activated by noxious thermal and mechanical stimuli. In the case of the former modality, we now suspect that a recently characterised receptor-channel (vanilloid receptor 1, VR1) that responds to capsaicin, the extract of hot peppers, may also be responsible for the generation of action potentials after application of heat. Although the endogenous ligand for this receptor is unclear, it may be anandamide, the cannabinoid. The peripheral terminals of small-diameter neurons, especially in conditions of tissue damage like inflammation, are excited by a number of endogenous chemical mediators. These can be released from local non-neuronal cells, the afferent fibres themselves, and from products triggered by activation of the body's defence mechanisms. These chemical mediators then interact to sensitise nociceptors so that afferent activity to a given stimulus is increased. This is known as primary hyperalgesia.

Some of the most important components in inflammation are the products of arachi-donic acid metabolism. Arachidonic acid, a component of cell membranes, is liberated by phospholipase A2 and subsequently metabolised by two main pathways which are controlled by two different enzymes, cyclo-oxygenase (COX) and lipoxygenase. This metabolism gives rise to a large number of eicosanoids (leukotrienes, thromboxanes, prostacyclins and prostaglandins) (see Chapter 13). These chemicals do not normally activate nociceptors directly but, by contrast, reduce the C-fibre threshold and so sensitise them to other mediators and stimuli. Thus the value of both steroids and the non-steroidal anti-inflammatory (NSAIDs) drugs in pain after tissue damage is based on their ability to block the conversion of arachidonic acid to these mediators. It should be emphasised that these drugs can only prevent further conversion and will not change the effects of eicosanoids that have already been produced. The short half-life of these mediators makes this fact less important than it would be if the mediators had long-lasting effects. Importantly, a second inducible form of COX, COX-2, has been described. COX occurs in two isoforms, 1 and 2. The former is a constitutive enzyme, always present so that its inhibition affects not only inflammation but also other actions of the products leading to gastric and renal side-effects. By contrast, COX-2 is induced in the periphery by tissue damage and a new generation of selective COX-2 inhibitors have improved therapeutic profiles over existing non-selective drugs. Several novel agents with actions on this latter enzyme are effective in inflammatory pain. Interestingly, COX-2 is normally present in the brain and spinal cord and so may be responsible for some of the central analgesic effects of NSAIDs.

Bradykinin is another chemical with important peripheral actions but, as yet, cannot be manipulated in any direct way by drugs. It is a product of plasma kininogens that find their way to C-fibre endings following plasma extravasation in response to tissue injury. Bradykinin receptors have been characterised and here again, there are two forms. The Bi-receptor is constitutively expressed less than the B2-receptor, but in chronic inflammation, it is upregulated. Pain may arise via the activation of the B2-receptor, which is abundant in most tissues and which can activate C-polymodal receptors. The response to bradykinin can be enhanced by prostaglandins, heat and serotonin, indicating the extent of interactions between these peripheral pain mediators.

Hydrogen ions accumulate in tissue damaged by inflammation and ischaemia and so pH is lowered. These protons may activate nociceptors directly via their own family of ion channels as well as sensitising them to mechanical stimulation. Acid-sensing ion channels (ASICS) are a family of sodium channels that are activated by protons — of special interest is one type found only in small dorsal root ganglion neurons that possibly are responsible for activation of nociceptors. Although the transduction of mechanical stimuli is poorly understood, ASICs are closely related to channels that respond to stretch.

VASCULAR DAMAGE, HEADACHE AND MIGRAINE

Serotonin, 5-hydroxytryptamine (5-HT), is released from a number of non-neuronal cells such as platelets and mast cells and can produce an excitation of nociceptive afferents via the activation of its large number of receptors, e.g. 5-HTiA, 5-HT2 and 5-HT3 as well as sensitising nociceptors, especially to bradykinin. The key role, but not the mechanisms of action, of 5-HT in the pain associated with migraine and other headaches is well established but little is known about the actions of this mediator in other non-cranial pains. The aura of neurological symptoms and/or signs in migraine is thought to be caused by a vascular or a neuronal mechanism, or a combination of the two. One theory suggests that changes in the vasculature are responsible for causing migraine whereas a second theory proposes that the vascular changes only mediate the pain and symptoms of migraine. A third theory suggests the primary abnormality is neuronal and originates within the brain itself.

The original hypothesis was that vasoconstriction of intracranial vessels leads to a reduced blood flow, which results in cerebral hypoxia. If the arterioles are constricted sufficiently to cause a reduction in regional cerebral blood flow (rCBF), the brain tissue is hypoperfused, which can cause neurological deficits thought to be responsible for the 'aura'. Wolff, who proposed this idea, stated that following the vasoconstriction of the cranial vessels, vasodilatation of these vessels occurred which gave rise to the pain (via the stretching of nerve endings in the vascular walls), and which also resulted in a change in regional cerebral blood flow. There are some weaknesses in the theory that the primary problem is within the vasculature. As the progression of the symptoms does not respect vascular territories it is unlikely to be primarily due to spasm within the vasculature. The blood flow changes are more consistent with a primary neuronal event causing secondary vascular changes. Another factor that makes the theory of a primary vascular abnormality untenable is that the headache may begin while cortical blood flow is still reduced.

A related idea is that peripheral nerves are the source of the problem and then cause the associated vascular changes via release of 5-HT and other inflammatory mediators. The observation that the changes in the vasculature do not follow vascular anatomy has led to a new theory, that of 'spreading depression'. Here, the primary abnormality is within the brain itself, a spreading decrease in electrical activity, that moves at a rate of 2-3mm/min from the site of origin across the cortex. This transient wavefront suppresses both evoked and spontaneous neuronal activity. In spreading depression, the depolarisation is limited to one hemisphere, and there is a refractory period for further spreading depression of up to 3 min. Any decrease in neuronal firing leads to an increase in metabolism which would result in a decrease in rCBF, via autoregulation.

Sumatriptan is an agonist at 5-HTiB and 5-HT1D receptors. It has three distinct pharmacological actions.

Stimulation of the presynaptic inhibitory 5-HT1D receptors on trigeminal A^-fibres inhibits the release of calcitonin gene related peptide (CGRP) which on release forms peripheral ends of sensory fibres via the antidromic axon reflex, causes vasodilatation. Sumatriptan therefore inhibits dural vasodilatation. 5-HT1D receptors on trigeminal C-fibres are also activated by the drug, inhibiting the release of substance P (SP) and neurokinin A (NKA) and therefore blocking neurogenic inflammation and dural plasma extravasation.

Direct attenuation of the excitability of neurons in the trigeminal nuclei, as 5-HT1B/ 5-HTjD receptors on pain transmission neurons in the trigeminal nucleus caudalis and in the upper cervical cord, are activated. Stimulation of these receptors is caused by second-generation triptans that cross the blood-brain barrier such as zolmitriptan, naratriptan, rizatriptan and eletriptan.

Direct vasoconstriction is mediated by the stimulation of vascular 5-HT1B receptors. These receptors are also found systemically, so coronary arteries also undergo vasoconstriction. Sumatriptan constricts cerebral arteries, but if the vasculature is normal, this does not affect rCBF.

Mast cells, as well as releasing 5-HT, can also release histamine which causes vasodilatation, oedema and itch and ATP and adenosine are also involved in inflammatory conditions. Substance P and CGRP released from the peripheral terminals of primary afferents (via axon reflex) can also cause the mast cells to degranulate and release 5-HT. The peptides cause a number of effects including vasodilatation, plasma extravasation and mast cell degranulation and ATP can result in a direct nociceptor activation via activation of P2X receptors. Other factors such as Nerve Growth Factor (NGF) and cytokines are also important at the peripheral level and resultant changes in the phenotype of the sensory neurons have been shown to be one of the resultant effects. Thus, NGF is upregulated in the area of tissue damage and then binds to its high-affinity receptor, the trkA receptor, one of the tyrosine kinase family. NGF and the receptor are then internalised and transported to the cell body in the dorsal root ganglion. Here, there is a resultant change in gene expression so that the gene for pre-pro tachykinins is turned on. Thus tissue damage causes complex changes in the transduction of painful stimuli. Figure 21.1 shows some of the mediators at the peripheral level with their receptors.

NERVE DAMAGE

Neuropathic pain states are thought to be generated in the peripheral sensory neurons by events within the nerve itself and so are independent of peripheral nociceptor activation. Damage to peripheral nerves can be caused by a number of pathological, metabolic and viral causes. According to the terminology guide of the International

Peripheral Pain
Figure 21.1 Some of the mediators of pain at the peripheral level with their receptors. Note that with regard to 5-HT, the cranial mechanisms have been omitted for clarity

Association of Pain, neuropathic pain is defined as'pain initiated or caused by a primary lesion, dysfunction in the nervous system'. Neuropathy can be divided broadly into peripheral and central neuropathic pain, depending on whether the primary lesion or dysfunction is situated in the peripheral or central nervous system. In the periphery, neuropathic pain can result from disease or inflammatory states that affect peripheral nerves (e.g. diabetes mellitus, herpes zoster, HIV) or alternatively due to neuroma formation (amputation, nerve transection), nerve compression (e.g. tumours, entrapment) or other injuries (e.g. nerve crush, trauma). Central pain syndromes, on the other hand, result from alterations in different regions of the brain or the spinal cord. Examples include tumour or trauma affecting particular CNS structures (e.g. brainstem and thalamus) or spinal cord injury. Both the symptoms and origins of neuropathic pain are extremely diverse. Due to this variability, neuropathic pain syndromes are often difficult to treat. Some of the clinical symptoms associated with this condition include spontaneous pain, tactile allodynia (touch-evoked pain), hyperalgesia (enhanced responses to a painful stimulus) and sensory deficits.

Neuropathy elicits a number of changes in nerves, in terms of activity, properties and transmitter content. The recent advent of a number of animal models of neuropathic pain states has facilitated understanding of the peripheral mechanisms involved. Damaged nerves may start to generate ongoing ectopic activity due to the accumulation and clustering of sodium channels around the damaged axons and there is also evidence that mechanoreceptors become highly sensitive to applied stimuli. This aberrant activity can then start to spread rapidly to the cell body in the dorsal root ganglia. Nerve fibres can start to cross-excite each other and the same occurs in the cell bodies.

In addition to changes within the nerve, sympathetic afferents become able to activate sensory afferents via as yet poorly characterised a-adrenoceptors. These interactions between adjacent sensory and autonomic nerve axons and between ganglion cells result in excitation spreading between different nerve fibres. These peripheral ectopic impulses can cause spontaneous pain and prime the spinal cord to exhibit enhanced evoked responses to stimuli, which themselves have greater effects due to increased sensitivity of the peripheral nerves.

This peripheral activity may be a rational basis for the use of systemic local anaesthetics in neuropathic states since ectopic activity in damaged nerves has been shown to be highly sensitive to systemic sodium channel blockers. This too is probably part of the basis for the analgesic effects of established effective anti-convulsants that block sodium channels such as carbamazepine, although central actions are important and may even predominate. The precise actions of excitability blockers therefore remains hazy as does any clear basis for the effectiveness of antidepressants and other adrenergic agents in the treatment of neuropathic pain as both central and peripheral actions, including sympathetic effects are possible.

It has been clearly shown recently that C-fibres can generate action potentials via unique sodium channels with very low TTX sensitivity that are different from those found in other tissues. These channels may become important targets for drugs in neuropathic and other pains since a systemic agent with selectivity for those channels would only block C-fibre activity. However, a complex regulation of these channels after nerve injury makes appraisal of their place in the control of this type of pain difficult — the TTX-resistant channels translocate from the cell bodies of the injured nerves to the site of injury and yet are upregulated in adjacent ganglia. Furthermore, TTX-sensitive channels also upregulate and a novel channel is induced.

Continue reading here: Central Events In The Transmission Of Pain

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