Mechanisms of Pain in Nonmalignant Disease Victoria L

Mechanisms of pain in nonmalignant disease Victoria L. Harvey and Anthony H. Dickenson

Department of Pharmacology, University College Purpose of review London, London, UK To review key mechanisms underlying the transmission of nociceptive information from Correspondence to Victoria L. Harvey, Department of the periphery to the central nervous system implicated in different acute pain states. Pharmacology, University College London, Gower St, London, WC1E 6BT, UK Recent ﬁndings E-mail: [email protected] Advances in molecular and transgenic approaches have helped to identify novel therapeutic targets for the treatment of pain from tissue and nerve damage such as acid-

Current Opinion in Supportive and Palliative sensing ion channels, transient receptor potential and NaV channels. The subsequent Care 2008, 2:133–139 development of selective pharmacological ligands has also strengthened the role of other receptors such as hyperpolarization-activated cyclic nucleotide-gated channels and the further development of subunit speciﬁc antagonists, such as those available for NR2B, will further advance our understanding of the mechanisms involved in nociceptive transmission. Summary Inﬂammatory and neuropathic pain differ considerably in their peripheral mechanisms but certain central spinal and brain mechanisms are common to both. The mechanisms of pain are not fully established but are thought to be underpinned by changes in the expression of receptors (nociceptive plasticity), central spinal hyperexcitability (central sensitization) and alterations in descending control from the midbrain. This review considers these mechanisms and highlights recent advances in the understanding of pain perception.

Keywords dorsal horn, facilitation, inﬂammatory pain, neuropathic pain, plasticity

Curr Opin Support Palliat Care 2:133–139 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins 1751-4258

Characteristic symptoms experienced with pain, resulting Introduction from these various causes, include an increased amplitude Pain, although generally initiated by damaging events of response to a given stimulus (hyperalgesia), pain elicited within the body and subsequently transmitted into the by normally innocuous stimuli (allodynia) and spon- central nervous system, can also be generated within taneous pain in the absence of external stimuli. Sensory central nervous system circuits such as post-stroke pain. deficits can also exist in neuropathic pain. In addition, as This account will consider various peripherally gener- pain persists, even over short periods there are the affective ated acute pains, a series of heterogeneous conditions and emotional responses that have to be considered along involving a cohort of neuronal mechanisms. These pain with the sensory aspects of the stimulus. The sensory and states can be broadly categorized into those accompany- psychological aspects of pain are separable in terms of ing tissue damage (trauma, surgery, tumour growth and pathways within the central nervous system but there is an arthritic conditions) and those following nerve damage interplay between the neural pathways that contribute to caused again by trauma, surgery, tumours and also these components. It is clear from these symptoms that at viruses (postherpetic neuralgia, HIV) and metabolic both peripheral and central sites, there are mechanisms disorderssuchasdiabetes.The inflammatory and neuro- that can amplify and prolong the experience of a painful pathic pains differ considerably in their peripheral stimulus and a miscoding of normally innocuous stimuli – mechanisms but share more common central spinal this can result in severe pain in the presence of a relatively and brain mechanisms. Current research emphasis minor peripheral disorder. envelops the nociceptive plasticity of ion channels at peripheral (e.g. sodium channels) and central sites (e.g. calcium channels), central spinal hyperexcitability Tissue damage (central sensitization) and alterations in descending con- Peripheral sensory nerve fibres are divided into A-fibres in trol from the midbrain. which A-b fibres normally convey innocuous information

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and A-d fibres that can respond to noxious mechanical play a major role in the maintenance of pain arising from stimuli and a population of C-fibres that respond to a wide tissue or nerve inflammation [11–13]. Although 5-HT has range of noxious stimuli. The latter groups respond to been identified as playing a key role in the pain associated acute noxious mechanical and thermal stimuli and are with migraine, its mechanism of action is less clear and sensitized by tissue damage. Tissue damage elicits the is not known whether changes in this mediator are per- release of a number of endogenous chemical mediators at ipherally or centrally driven [14]. 5-HT3 receptors, when both peripheral and central sites. Of these, prostaglandins activated, cause pain [15] and antagonists (e.g. ondanse- (in particular PGE2) represent an important component of tron) have been shown to possess peripheral analgesic inflammation, sensitizing primary afferent fibres to other actions in human studies. ATP is present in all cells so key mediators and stimuli and reducing their thresholds tissue damage rapidly causes a marked rise in extracellular so that they now respond to lower intensity stimuli levels of this purine that is a potent algogen. Of the 7 P2X (peripheral sensitization). Steroids and nonsteroidal anti- receptors for ATP cloned to date, P2X3 homomeric and inflammatory drugs (NSAIDs) are able to block cyclo- PX2X2/3 heteromeric receptors are expressed in unmye- oxygenase (COX), an enzyme upstream of the produc- linated sensory neurons wherein they sense ATP release tion of prostaglandins [1]. Classically, NSAIDs inhibit following injury to the surrounding tissues [16]. Following the constitutive isoform (COX-1) and subsequently lead inflammation, P2X3 receptors enhance neurotransmitter to gastrointestinal complications. More recently, a second release either through an upregulation of their expression inducible form (COX-2) with a different pattern of distri- or through receptor sensitization [17,18]. Further support bution had been described [2]. Although COX-2 inhibitors for the importance of these channels comes from antisense have avoided the gastropathy associated with COX-1 studies in which P2X3 receptor knockdown with siRNAs inhibition, increased cardiovascular complications have attenuated nocifensive behaviour in rats following an been described and their therapeutic gain is now unas- inflammatory or neuropathic insult [19,20]. sured [3]. Central targets downstream of PGE2 have been identified to be important in inflammatory pain. COX-1 Capsaicin, the hot ingredient in chilli peppers, evokes a and COX-2 are present and upregulated in the spinal cord sensation of burning pain thought to occur from the and prostaglandins can be released at this level, indicative activation of TRPV1 (VR1), a receptor thought originally of a role of centrally penetrating NSAIDs in pain control. to represent the sole molecular identity of our heat sensor Interestingly, spinal GlyRa3 receptors are thought to be [21]. Since then 27 transient receptor potential (TRP) selectively inhibited through the phosphorylation of a channels have been cloned in humans [22], and a subset key serine (S346), which is not present in the other major of these (thermoTRPs) are thought responsible for ther- adult spinal isoform (a1) [4]. The distinct expression pat- mal signalling [23]. Of these, transgenic studies [21,24] tern of the GlyRa3 receptors in lamina II of the dorsal horn have revealed that TRPV1 is required for the thermal suggests that such a disinhibition could lead to facilitated hypersensitivity observed in inflammation, and TRPM8 nociceptive transmission in response to inflammation. is important in cold hypersensitivity in neuropathy and inflammation [25]. In addition to thermal signalling, Bradykinin, hydrogen ions, ATP and 5-HT also accumu- TRP channels may also serve as receptor-operated chan- late in damaged tissue, and cause acidosis, vasodilation and nels, such as TRPA1 that depolarizes nociceptors in plasma extravasation causing the oedema and vasodilata- response to proalgesic and proinflammatory agents that tion that occur in inflammation. Acid-sensing ion channels activate phospholipase C (PLC)-signalling pathways (ASICs), due to their location and properties are likely [26,27]. candidates for Hþ-gated nociceptors, sensing tissue acidosis in response to inflammation [5]. Upregulation of ASIC The interplay between these numerous pain transducers subunit expression has been observed experimentally at C-fibre endings explains the commonly observed per- during inflammation [6] and inhibitors have displayed ipheral sensitization that occurs after tissue damage. efficacy in acid-induced pain in humans [7]. Furthermore, Although these multiple targets at peripheral levels are as inflammatory mediators such as nerve growth factor potential targets for novel analgesic therapies, the issue of (NGF), 5-hydroxytryptamine (5-HT), interleukin-1, bra- redundancy with multiple pain sensors is an important dykinin and brain-derived neurotrophic factor (BDNF) factor in decisions on which receptor to target. can upregulate ASIC transcription, these channels may contribute to the pronociceptive effects of these mediators [8]. Interestingly, increased expression of the proinflam- Nerve damage matory cytokine, tumour necrosis factor-a (TNF), in both Sodium channels generate the action potential. Follow- the dorsal root ganglia and the spinal cord has been ing damage to peripheral nerves, primary afferent fibres reported following several types of nerve injury [9,10]. often display aberrant ‘ectopic’ activity altering their The mechanisms involved are unclear but the downstream pattern of neuronal excitability and conduction causing activation of p38 mitogen-activated kinase is thought to spontaneous pain and hyperalgesia. These changes are

thought to arise namely through the accumulation of pain from varying origins [42–44]. Following nerve sodium channels at or around the site of injury. Although injury, a2d subunits are slowly upregulated in the central sodium channels have long been associated with terminals of peripheral nerves [45] possibly allowing GBP the efficacy of local anaesthetics such as lignocaine and and PGB to selectively inhibit abnormal neuronal the anticonvulsant carbemazepine they have, through the function associated with neuropathy [46–49]. A further generation of mutant mice, received renewed interest. In permissive factor in the actions of these drugs is particular, tetrodotoxin (TTX)-resistant Nav 1.8 and 1.9 activity in spinal 5-HT3 receptors, themselves driven channels are expressed almost exclusively in small, by activity in descending pathways from the brain – unmyelinated fibres, whereas TTX-sensitive Nav 1.7 this rapidly switching circuit may not only explain the channels are expressed in both sensory and sympathetic actions of a2d ligands after nerve injury but their acute neurons. Although it is likely that these ion channels are effects such as those seen after surgery. regulated by nerve and tissue damage, transgenic animals lacking 1.7 or 1.8 show marked reductions in neuronal Hyperpolarization-activated cyclic nucleotide-gated responses to acute noxious mechanical stimuli. Inherited (HCN) channels are predominantly located within the ‘gain of function’ mutations of SCN9A, the gene encod- cardiovascular system and DRG, wherein they are thought ing Nav 1.7, results in the rare autosomal dominant to generate spontaneous rhythmic activity as well as con- disease primary erythermalgia [28], whereas a ‘loss of tributing to neuronal excitability and plasticity [50]. Nerve function’ channelopathy produces analgesia [29]. damage elicits a marked increase in the expression of particularly HCN1 channels in large diameter afferents The biophysical properties of Nav 1.8 currents permits evoking spontaneous pacemaker-driven action potentials them to participate in action potential electrogenesis in the damaged nerve [51]. Further studies [52] with an even at potentials close to 40 mV, which can occur HCN antagonist (ZD7288) reversed behavioural mecha- following nerve injury [30] and more recently have been nical hypersensitivities in animals with experimentally identified in signalling cold-induced pain [31]. Nav 1.3, a induced neuropathic (spinal nerve ligation, SNL) and mild TTX-sensitive channel, is developmentally regulated thermal injury (MTI) pain. wherein expression is primarily associated with embryo- nic development and, under normal conditions, declines to low levels following birth. Following peripheral nerve Central excitatory mechanisms damage Nav 1.3 levels in dorsal root ganglia increase, and Ad and C fibres terminate primarily in the superficial the biophysical properties of these channels suggests that laminae of the dorsal horn, namely lamina I, wherein they are capable of supporting ectopic neuronal firing the large majority of neurones are nociceptive specific [32–36]. Recently, Jarvis et al. [37] have demonstrated with small receptive fields, responding to only noxious the efficacy of the first Nav 1.8 selective antagonist pinch and/or heat stimulation and with major outputs to (A-803467) in a variety of animal models of inflammatory the brain. A smaller population of polymodal (HPC) and neuropathic pain. neurones are found that are also cold responsive. Lamina I neurones have been shown to project to areas such as the Although sodium channels act as the accelerator, potas- periaqueductal grey (PAG), lateral parabrachial nucleus, sium channels serve as the molecular brakes of the system, thalamus, nucleus tractus solitarius (NTS) and the medul- playing an important role in modulating neuronal lary reticular formation. A large number of projection hyperexcitability. In particular, spinally applied retiga- neurones from lamina I express the receptor for substance bine, a KCNQ channel (KV7, M-current) opener, inhibits P, NK1 [53]. This group of neurones is the origin from C-mediated and Ad-mediated responses in dorsal horn which a spinobulbospinal loop originates that drives des- neurones in both naı¨ve and neuropathic rats [38], and cending controls and can set dorsal horn excitability from diminishes behavioural hypersensitivity in neuropathic higher centres. Within deeper lamina V, neurones are rats [39]. More recently, TREK-1, a member of the two- wide-dynamic range, responding to both innocuous and þ pore-domain K channel family (K2P), has been found in noxious stimuli, exhibiting wind-up and projecting to small sensory neurones and colocalizes with TRPV1 [40]. sensory areas of the brain such as the thalamus. Both Knockout mouse studies [40] have revealed a role for this the lamina I and V neurones therefore provide parallel receptor in polymodal pain, and studies [41] in transfected outputs to the sensory and affective areas of the brain. cell lines have suggested a role in anaesthesia as it is There is clear evidence from both preclinical and clinical activated by volatile anaesthetics. studies that apart from peripheral processes, central hyperexcitability plays important roles in determining the level Gabapentin (GBP) and pregabalin (PGB), which attenu- of pain perceived. ate neurotransmitter release through binding to the a2d subunit of voltage-gated Ca channels, have demonstrated Neurones of the dorsal horn of the spinal cord represent a their value in the treatment of peripheral neuropathic key modulatory site for the processing of nociceptive

information. The major excitatory neurotransmitter glu- istration of ondansetron, a 5-HT3 antagonist, attenuates tamate is found in both primary afferent and projection 5-HT-mediated pronociception [65,66]. Furthermore, this neurones. Glutamate acts at both the metabotropic descending hyperalgesic serotinergic (5-HT3) pathway (mGlu) receptors G-protein coupled) and the ionotropic from the brainstem is permissive for the actions of GBP AMPA, Kainate and N-methyl-D-aspartic acid (NMDA) [67–69]. receptors (coupled directly to ion channels). During high frequency firing of C fibres, glutamate and its coreleased transmitter substance P cooperate to allow NMDA recep- Central inhibitory mechanisms tor activation, resulting in the wind-up of dorsal horn Morphine and fentanyl, mu (m) opioid receptor agonists, neurones. Neurones rapidly switch from a constant low- remain the gold standard for the treatment of moderate level response to a higher prolonged and amplified level and severe pain. These receptors represent the of activity. This has been reported in a wide range of endogenous system for the suppression of pain. Expres- human acute and persistent pain conditions. This sion studies have shown that opioid receptors (m, d, k process is thought to underpin central sensitization, and ORL1) are predominantly expressed in the super- whereby nociceptive pathways display increased ficial laminae (I and II) of the spinal cord wherein synaptic efficacy (LTP) and is thought to represent nociceptive primary afferents terminate [70], and their the mechanism responsible for hyperalgesia and allody- expression is differentially regulated following neuro- nia [54]. First generation NMDA anatagonists such as pathy and inflammation [71–74]. Their principal actions ketamine, memantine and dextromethorphan are still involve the presynaptic attenuation on neurotransmitter well used today in a wide variety of pain states [55–58], release by inhibition of voltage-gated calcium channels although their long-term use is more limited due to and postsynaptic inhibition of projection neurones their cognitive contraindications. Alternative subunit through the activation of G protein-regulated inwardly specific regimes are being investigated such as NR2B rectifying Kþ (GIRK) channels [75,76]. The supraspinal antagonism with ifenprodil, as these subunits are activity of opioids, in areas such as the rostroventral specifically upregulated following nerve injury in medulla (RVM), PAG matter and the locus coeruleus animals [59]. disinhibit spinally projecting noradrenergic and serotonergic fibres possibly through the inhibition of presyn- Genes are rapidly switched on in spinal neurones follow- aptic g-aminobutyric acid (GABA) receptors [77,78]. A ing intense acute noxious stimuli including genes role for nociceptin, the endogenous ligand for mor- thought to be important in forebrain memory processes phine-resistant ORL1 receptors, has been demonstrated such as zif 268. These more enduring changes in synaptic in animal models of neuropathic and inflammatory pain events may be a process that could lead to the transition [79–81]. Furthermore, ORL1 receptors are thought to from acute to chronic pain. form unique complexes with CaV2.2 channels such that prolonged exposure to nociceptin triggers a protein Alterations in both the transmission of nociceptive infor- kinase C-dependent internalization of the ORL1/ 2þ mation within the spinal cord and the changes in the CaV2.2 complex, thus downregulating Ca channel descending controls, which relay information from higher activity [82]. brain centres to the spinal cord, are frequently observed in pain states. These pathways are highly complex in nature and also involve supraspinal centres, such as those Conclusion associated with affective-cognitive information process- It is evident from the literature that the mechanisms ing. Increased activity within the spinal NK1-receptor- underlying pain perception are highly complex in nature driven spino-bulbo-spinal loop is associated with patho- involving the plasticity and functional dysregulation of physiology [60]. NK1-receptor expressing lamina 1 numerous ion channels and receptors within both the neurones are predominantly projection neurones that peripheral and the central nervous system (Fig. 1). These terminate in a number of brainstem areas involved in changes underlie alterations in the transmission and both the sensory and the affective components of processing of nociceptive information resulting in pain nociception [53]. These areas are the key sites for the related phenomena such as ectopic neuronal discharge, descending noradrenergic and serotonergic controls that peripheral and central hyperexcitability and the facili- regulate spinal nociceptive processing and underlie the tation of descending algogenic pathways. efficacy of antidepressants for the treatment of pain [61,62]. Modulation of descending serotonergic pathways Advances in molecular and genomic techniques continue is, however, complex as the release of 5-HT can lead to to identify novel therapeutic targets; the subsequent both antinociception and pronociception [63,64] and most development of more selective and subtype specific likely depends on the activation of specific receptor sub- ligands will greater advance our understanding of the types. The depletion of spinal 5-HT or intrathecal admin- mechanisms of pain.

Figure 1 Pathophysiological changes in nociceptive transmission

Thalamus cortex

Limbic Peripheral insult PAG system Inflammatory mediators Na+, HCN channel plasticity Parabrachial RVM area Transcription/ function: ASIC 5-HT3-R P2X3 + TRPV1 + Prostaglandin Spontaneous Spinal activity EP neurone 2 -- Ca2+ Inhibitory channel GlyRα3 interneurone function function NMDA-R function

Damage and/or inﬂammation in the periphery evoke changes in the transcription and function of channels and receptors in both the peripheral and the central nervous systems. This leads to an increase in the output of spinal neurones that project to higher centres of the brain that, in turn, engage descending pathways from the periaqueductal grey (PAG) and the rostroventral medulla (RVM). These synapse on dorsal horn neurones and further facilitate nociceptive transmission. ASIC, acid sensing ion channels; EP2, prostaglandin E2 receptor; GlyRa3, glycine a 3 receptor; HCN, cyclic nucleotide-gated ion channel; NMDA-R, N-methyl-D-aspartic acid receptor; TRPV, transient receptor potential ion channel.

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