The importance of genetic background on pain behaviours and pharmacological sensitivity in the rat spared serve injury model of peripheral neuropathic pain.

Neuropathic pain conditions can encompass a diverse constellation of signs and symptoms consisting of sensory deficits, allodynia and hyperalgesia. Animal models of neuropathic pain have enabled the identification of key pathophysiological changes occurring within nociceptive pathways as a result of injury, and serve an invaluable role for preclinical screening of novel analgesic candidates. We have produced the first systematic description of the development and maintenance, and the pharmacological sensitivity of nociceptive behaviours in four rat strains with different genetic background (outbred Sprague-Dawley and inbred Brown Norway, Lewis and Fischer 344 rats), using the spared nerve injury model of peripheral neuropathic pain. Hindpaw mechanical hypersensitivity was evident from 7 to 30 days post-injury in all four strains, developing most quickly and severely in Fischer 344 rats; Lewis rats were least affected. Morphine (6 but not 3 mg/kg, s.c.) and gabapentin (100 but not 50 mg/kg, s.c.) had significant antiallodynic and antihyperalgesic actions in all four strains after spared nerve injury, although marked differences in potency across strains were observed. Two strains (Fischer 344 rats and Lewis) were insensitive to the antihyperalgesic properties of gaboxadol (15 mg/kg) whereas gaboxadol (6 mg/kg) was equipotent to morphine (6 mg/kg) in two other strains (Sprague-Dawley and Brown Norway). The observed pharmacogenetic variations have important implications for the preclinical testing of drugs, and provide a basis for development of pharmacogenomics in neuropathic pain.

Pharmacological characterisation of place escape/avoidance behaviour in the rat chronic constriction injury model of neuropathic pain.

RATIONALE: Classical pain tests performed in animals routinely measure evoked nociceptive behaviours. These almost exclusively reflect sensory processing of nociceptive transmission, although a recently described place escape/avoidance paradigm may be used to selectively assess affective pain processing. OBJECTIVE: To establish if drugs with proven analgesic efficacy selectively attenuate sensory-discriminative or affective-motivational aspects of nociceptive processing. METHODS: The mu-opioid receptor agonist morphine, the anti-epileptic gabapentin, the anti-depressant duloxetine, the 5HT1A receptor agonist 8-OH-DPAT, the GABA(A) receptor agonist gaboxadol and the mixed cannabinoid receptor agonist WIN55,212-2 were tested after systemic administration in the chronic constriction injury (CCI) model of neuropathic pain. For the place escape/avoidance paradigm, CCI rats had free access between the 'non-aversive' dark and 'aversive' light side of an enclosed chamber. Either the injured or non-injured hindpaw was routinely stimulated if the rat was in the dark or light area, respectively. Escape/avoidance behaviour was defined as a shift from the dark to the light area. Mechanical allodynia and hyperalgesia were determined prior to and following escape/avoidance testing. RESULTS: Morphine (3 and 6 mg/kg), gabapentin (50 and 100 mg/kg), duloxetine (10 and 30 mg/kg) and 8-OH-DPAT (0.1 and 0.5 mg/kg) attenuated the time spent by CCI rats in the light area; gaboxadol (1 and 3 mg/kg) and WIN55,212-2 (0.3 and 1 mg/kg) were ineffective. Only gabapentin and 8-OH-DPAT attenuated mechanical nociceptive behaviours at non-sedative doses. CONCLUSIONS: The place escape/avoidance paradigm may enable discrimination between selected drug classes on distinct components of sensory and affective pain processing in rats with neuropathic pain.

Venlafaxine compromises the antinociceptive actions of gabapentin in rat models of neuropathic and persistent pain.

RATIONALE: Neuropathic pain is associated with a number of disease states of diverse aetiology that can share common pathophysiological mechanisms. Antiepileptic drugs modulate ion channel function and antidepressants increase extracellular monoamine levels, and both drug classes variously attenuate signs and symptoms of neuropathic pain. Thus, coadministration of the antiepileptic gabapentin and the antidepressant venlafaxine may provide superior pain relief to administration of either drug alone. OBJECTIVES: To systematically establish the pain relieving efficacies of venlafaxine and gabapentin alone and in combination. MATERIALS AND METHODS: Gabapentin (50 and 100 mg/kg, s.c.) and venlafaxine (10, 25, 50 mg/kg, s.c.) were tested alone or in combination in the rat spared nerve injury (SNI) model of neuropathic pain and the rat formalin test of persistent pain. Diuresis was measured in a separate experiment after administration of venlafaxine. RESULTS: Hindpaw mechanical allodynia was dose-dependently reversed by gabapentin (50 and 100 mg/kg, s.c.), whereas venlafaxine was ineffective (10 and 50 mg/kg, s.c.). Both gabapentin and venlafaxine also attenuated hindpaw mechanical hyperalgesia. Surprisingly, coadministration of venlafaxine (50 mg/kg) significantly lowered the antiallodynic effect of both doses of gabapentin by up to 60% in spared-nerve-injury rats and a negative antinociceptive interaction between gabapentin and venlafaxine was also observed in the rat formalin test. We demonstrated that venlafaxine administration was associated with a dose-dependent increase in urine output over the time course of the nociceptive experiments. CONCLUSION: Venlafaxine compromises the antiallodynic effects of coadministered gabapentin most probably as consequence-increased diuresis.

A role of the ubiquitin-proteasome system in neuropathic pain.

Neuropathic pain (characterized by hyperalgesia and allodynia to mechanical and thermal stimuli) causes cellular changes in spinal dorsal horn neurons, some of which parallel those in synaptic plasticity associated with learning. Ubiquitin C-terminal hydrolase (UCH) appears to play a key role in long-term facilitation in Aplysia. The cooperation of UCH with the proteolytic enzyme complex known as the proteasome is required for the degradation of a number of signaling molecules within the cell that may remove normal restraints on synaptic plasticity. We have used electrophysiology, in situ hybridization histochemistry, semiquantitative RT-PCR, Western blotting, and in vivo behavioral reflex analysis to investigate the ubiquitin-proteasome system in a model of neuropathic pain. In neuropathic animals, ionophoretic application of selective proteasome inhibitors attenuated dorsal horn neuron firing evoked by normally innocuous brush or cold stimuli and by noxious mustard oil stimuli. In control animals, only mustard oil-evoked responses were inhibited. Intrathecal administration of proteasome inhibitors attenuated hyperalgesia and allodynia in neuropathic rats. Expression of UCH-L1 (a rat homolog of Aplysia neuronal UCH and of the human UCH-L1, also known as PGP 9.5) and its mRNA were selectively increased within the ipsilateral dorsal horn of neuropathic rats, supporting the idea of a role for the ubiquitin-proteasome system in nociceptive processing. Proteasome inhibitors selectively attenuate allodynic and hyperalgesic responses in neuropathic pain, with some reduction in normal nociceptive, but not non-nociceptive responses, and potentially represent a novel therapeutic strategy for neuropathic pain.

Pain-like behaviours in animals - how human are they?

The use of genetically manipulated animals in conjunction with classical physiological and biochemical measurement has unravelled many pathological changes in animal models of chronic pain that bear some striking similarities to those described in several chronic pain conditions in humans. In this article, I highlight several limitations in the validation of animal models of chronic pain and the methods that are used for assessing pain-like behaviours in these models. Alternative methods for assessing pain and stress in animals, which might better reflect the diverse symptomotology of chronic pain in humans, are proposed.

Comparative actions of the opioid analgesics morphine, methadone and codeine in rat models of peripheral and central neuropathic pain.

Controversy persists in relation to the analgesic efficacy of opioids in neuropathic pain. In the present study the effects of acute, subcutaneous administration of the mu-opioid receptor agonists morphine, methadone and codeine were examined in rat models of peripheral and central neuropathic pain. In the spared nerve injury (SNI) and chronic constriction injury (CCI) models of peripheral neuropathic pain, both morphine (6mg/kg) and methadone (3mg/kg) attenuated mechanical allodynia, mechanical hyperalgesia and cold allodynia for up to 1.5h post-injection (P<0.05); codeine (30mg/kg) minimally alleviated mechanical hypersensitivity in SNI, but not CCI rats. When administered to rats with photochemically-induced spinal cord injury (SCI), morphine (2 and 6mg/kg) and methadone (0.5-3mg/kg) robustly attenuated mechanical and cold allodynia for at least 2h post-injection (P<0.05). Codeine (10 and 30mg/kg) also attenuated mechanical and cold allodynia in this model for at least 3h after injection. The magnitude of opioid-mediated antinociception was similar between SNI, SCI and non-injured rats as measured in the tail flick test. At antinociceptive doses, no motor impairment as determined by the rotarod test was observed. The therapeutic window (based on antiallodynia versus ataxia) obtained for codeine, was vastly superior to that obtained with morphine or methadone in SNI and SCI rats. Furthermore, the therapeutic window for codeine in SCI rats was 4-fold greater than in SNI rats. Our results further support the efficacy of mu-opioid receptor agonists in alleviating signs of neuropathic pain in animal models of peripheral and especially central nerve injury.

Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain.

The effects of acute, systemic administration of amitriptyline, duloxetine and mirtazapine (antidepressant drugs that variously affect extracellular noradrenaline and serotonin levels) and the selective serotonin reuptake inhibitor (SSRI) citalopram were compared in rat models of experimental pain. None of the drugs (all 3-30 mg/kg, i.p.) affected acute nociceptive responses as measured in the tail flick test. In the hot plate test, duloxetine and mirtazapine significantly increased (P<0.05) the nociceptive response latency, whereas amitriptyline and citalopram were ineffective. In the formalin test, duloxetine and citalopram significantly attenuated, whereas amitriptyline and mirtazapine increased, second phase flinching behaviour (all P<0.05). However, amitriptyline and mirtazapine reduced second phase licking behaviour. In the chronic constriction injury model of neuropathic pain, thermal hyperalgesia of the injured hindpaw was significantly attenuated by all four drugs (P<0.05); only amitriptyline and duloxetine fully reversed thermal hypersensitivity. None of the drugs tested attenuated mechanical allodynia. In contrast amitriptyline, duloxetine and mirtazapine significantly reduced mechanical hyperalgesia (P<0.05); citalopram was ineffective. No drug-related effects on motor performance in the rotarod test were observed. These results (a) highlight the difficulty in correlating antinociceptive effects of drugs from different antidepressant classes across a range of animal pain models and (b) suggest that antidepressants that variously affect both noradrenaline and serotonin levels have more potent and efficacious antinociceptive effects than SSRIs (as exemplified by citalopram), against a range of pain-like behaviours in an animal model of neuropathic pain.

Anti-nociception is selectively enhanced by parallel inhibition of multiple subtypes of monoamine transporters in rat models of persistent and neuropathic pain.

RATIONALE: Neuropathic pain is characterised by hyperexcitability within nociceptive pathways that manifests behaviourally as allodynia and hyperalgesia and remains difficult to treat with standard analgesics. However, antidepressants have shown reasonable preclinical and clinical anti-nociceptive efficacy against signs and symptoms of neuropathic pain. OBJECTIVES: To ascertain whether inhibition of serotonin (5-HT) and/or noradrenaline (NA) and/or dopamine (DA) re-uptake preferentially mediates superior anti-nociception in preclinical pain models. METHODS: The 5-HT re-uptake inhibitor fluoxetine (3-30 mg/kg), the NA re-uptake inhibitor reboxetine (3-30 mg/kg), the dual 5-HT and NA re-uptake inhibitor venlafaxine (3-100 mg/kg) and the dual DA and NA re-uptake inhibitor bupropion (3-30 mg/kg) were tested after intraperitoneal administration in rat models of acute, persistent and neuropathic pain. RESULTS: Reboxetine and venlafaxine dose-dependently attenuated second-phase flinching in the formalin test; fluoxetine attenuated flinching only at the highest dose tested, whereas bupropion was ineffective. In the chronic constriction injury (CCI) and spinal nerve ligation models of neuropathic pain, hindpaw mechanical allodynia was significantly attenuated by fluoxetine and particularly by bupropion. Reboxetine and venlafaxine were completely ineffective. In contrast, reboxetine and venlafaxine reversed thermal hyperalgesia in CCI rats, whereas bupropion and fluoxetine were either minimally effective or ineffective. Fluoxetine, reboxetine and venlafaxine transiently increased the tail-flick latency in uninjured animals. Anti-nociceptive doses of drugs had no effect on motor function. CONCLUSIONS: Combined re-uptake inhibition of 5-HT and NA appears to confer a greater degree of anti-nociception in animal models of experimental pain than single mechanism of action inhibitors. The selective attenuation of mechanical allodynia by bupropion suggests that the additional re-uptake of DA may further augment 5-HT/NA re-uptake mediated anti-nociception after nerve injury.

Normal hypothalamo-pituitary-adrenal axis function in a rat model of peripheral neuropathic pain.

Chronic pain conditions such as rheumatoid arthritis and fibromyalgia are associated with profound hypothalamo-pituitary-adrenal (HPA) axis dysfunction which may exacerbate symptoms of chronic pain. HPA axis dysfunction has also been well documented in animal models of chronic inflammatory pain. However, the role of the HPA axis in animal models of neuropathic pain is currently unknown. Rats with a chronic constriction injury (CCI) of the sciatic nerve that developed marked mechanical allodynia and hyperalgesia of the injured hindpaw were used to determine basal and stimulatory levels of HPA axis activity. Plasma ACTH and corticosterone levels were increased significantly (P < 0.05) in CCI rats after 20 min restraint stress compared with baseline; however, the magnitude of the increase was no different from sham rats. Furthermore, the temporal profile of ACTH release over the 60 min period after termination of restraint was similar between CCI and sham rats suggesting normal glucocorticoid-mediated feedback. Restraint stress also significantly increased (P < 0.05) expression of the immediate early genes c-Fos and FosB within the hypothalamic PVN to a similar extent in CCI and sham rats. Within the parvocellular PVN basal expression of both CRF and AVP mRNA was no different between CCI and sham rats; restraint stress induced a significant 2.5 fold increase (P < 0.05) in CRF mRNA expression in sham rats only. These results suggest that, in contrast to inflammatory immune-mediated pain models where HPA axis function is profoundly altered, in the CCI model of neuropathic pain, basal HPA axis function is unchanged. Furthermore, the HPA axis responds normally to a novel stressor in the face of ongoing nociceptive input, a stimulus known to activate the HPA axis.

Centrally-mediated antinociceptive actions of GABA(A) receptor agonists in the rat spared nerve injury model of neuropathic pain.

Gamma aminobutyric acid (GABA) plays a major role in the central hyperexcitabilty associated with nerve damage. The precise antinociceptive actions mediated by GABA(A) receptor agonists remain unclear as previous studies have shown mixed results in neuropathic pain models. Thus, various drugs which modulate GABA(A) receptor function were tested in the rat spared nerve injury (SNI) model of neuropathic pain. The selective GABA(A) receptor agonist gaboxadol dose-dependently (6 and 15 mg/kg, s.c.) reversed hindpaw mechanical allodynia and hyperalgesia for at least 150 min after administration. The GABA(A) receptor agonist muscimol (0.02-2 mg/kg, s.c.) also dose-dependently reversed mechanical allodynia, although the maximal effect achieved was less than that observed for gaboxadol. Mechanical hyperalgesia was attenuated only by the highest dose of muscimol. In contrast, the selective GABA(A) receptor agonist isoguvacine (20 mg/kg, s.c.) which has poor central nervous system penetration, and the benzodiazepine-site ligand zolpidem (20 mg/kg, s.c.) were ineffective against either nociceptive behaviour. In the rotarod test, both gaboxadol (15 mg/kg) and zolpidem impaired motor function for at least 60 min after injection; muscimol (2 mg/kg) and gaboxadol (6 mg/kg) were ineffective. Importantly, the ataxic effects induced by gaboxadol resolved 1-2 h after administration, a time point where clear antiallodynic and antihyperalgesic actions still occurred. Thus, systemic administration of blood-brain penetratable selective GABA(A) receptor agonists attenuate nociceptive behaviours in the SNI rat model of neuropathic pain that can be considered to occur independently of other effects on motor function.

Pain in the brain: are hormones to blame?

Pain is a multi-dimensional process involving the physical, emotional and perceptual integration of noxious information. The physical component is relayed via the spinal cord to several brain areas to initiate the detection of pain. The emotional aspect is encoded by the limbic system and encapsulates the relationship between pain and mood. Within the limbic system, the hypothalamus undertakes a diversity of separate and interrelated functions. Dysfunction of the hypothalamo-pituitary-adrenal axis has been implicated in a variety of chronic pain conditions and might also be associated with increased risk of developing mood disorders. Experimental and clinical evidence also exists to implicate the effects of other hormonal modulators in the manifestation of chronic pain. Specific targeting of hormonal cascade and effector mechanisms could provide an alternative strategy for the treatment of various chronic pain conditions.

Pharmacological characterisation of the spared nerve injury model of neuropathic pain.

The spared nerve injury (SNI) model involves a lesion of two of the three terminal branches of the sciatic nerve (tibial and common peroneal nerves) leaving the sural nerve intact. The changes in pain-like sensation of the injured animals appear to correlate with a number of symptoms presented in human patients with neuropathic pain syndromes. In order to characterise the SNI model pharmacologically, reflex nociceptive responses to mechanical and cold stimulation were measured after systemic administration of morphine, mexiletine, gabapentin and the glutamate receptor antagonists, MK-801 and NS1209. We observed that injection of morphine (6 mg/kg, s.c.) in non-sedative doses significantly attenuated mechanical hypersensitivity in response to von Frey hair and pin prick stimulation and cold hypersensitivity in response to ethyl chloride. The sodium-channel blocker, mexiletine (37.5 mg/kg, i.p.), relieved both cold allodynia and mechanical hyperalgesia, but the most distinct and prolonged effect was observed on mechanical allodynia. Gabapentin (100 mg/kg, i.p.) significantly alleviated mechanical allodynia for at least 3h, while no significant effects were observed for either mechanical hyperalgesia or cold allodynia. In contrast, the NMDA receptor antagonist MK-801 (0.1 mg/kg, i.p.) and the AMPA receptor antagonist NS1209 (6 mg/kg, i.p.) did not relieve any of the pain-like behaviours of the SNI animals. The present study has shown that a variety of drugs with proven analgesic potency in other models of chronic pain, have differing analgesic profiles in the SNI model of neuropathic pain.

Behavioural effects of the novel AMPA/GluR5 selective receptor antagonist NS1209 after systemic administration in animal models of experimental pain.

The effects of systemic administration of the novel AMPA/GluR5 selective receptor antagonist NS1209 in animal models of experimental pain have been tested and compared with the AMPA receptor antagonist NBQX and the opiate morphine. In the mouse hot plate test, NS1209 (3-30 mg/kg, s.c. and i.p.) and morphine (3-30 mg/kg, s.c.) significantly increased the nociceptive response latency, whereas NBQX (3-30 mg/kg, i.p.) was ineffective. In the rat formalin test, a model of persistent pain, NS1209 (3 and 6 mg/kg, i.p.) and morphine (0.5 and 3 mg/kg, s.c.) produced dose-dependent reductions in second phase nociceptive behaviours, although NBQX (10 and 20 mg/kg, i.p.) was without effect. In the chronic constriction injury model of neuropathic pain, NS1209 (3 and 6 mg/kg, i.p.), NBQX (10 and 20 mg/kg, i.p.) and morphine (3 and 6 mg/kg, s.c.) all reduced mechanical allodynia and hyperalgesia responses to von Frey hair and pin prick stimulation of the injured hindpaw. NS1209 and morphine also reduced cold hypersensitivity in response to ethyl chloride stimulation of the injured hindpaw. At the doses associated with anti-nociceptive actions, no effects on motor performance as determined by the rotarod test were observed for any of the drugs tested. Thus, systemic administration of NS1209 at non-ataxic doses has marked analgesic actions comparable to those of morphine in a range of animal models of experimental pain.

The anticonvulsant retigabine attenuates nociceptive behaviours in rat models of persistent and neuropathic pain.

We have tested for anti-nociceptive effects of the anticonvulsant KCNQ channel opener, N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester (retigabine), in rat models of experimental pain. In the chronic constriction injury and spared nerve models of neuropathic pain, injection of retigabine (5 and 20 mg/kg, p.o.) significantly attenuated (P<0.05) mechanical hypersensitivity in response to pin prick stimulation of the injured hindpaw. In contrast, retigabine had no effect on mechanical hypersensitivity to von Frey stimulation of the injured hindpaw in either model. Cold sensitivity in response to ethyl chloride was only attenuated (P<0.05) in the chronic constriction injury model. In the formalin test, retigabine (20 mg/kg, p.o.) attenuated flinching behaviour in the second phase compared with vehicle (P<0.05), and this effect was completely reversed by the KCNQ channel blocker 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE-991; 3 mg/kg, i.p.). Neither retigabine nor XE-991 administration affected the latency to respond to noxious thermal stimulation of the tail in control animals. These results suggest that retigabine may prove to be effective in the treatment of neuropathic pain.

Pharmacological characterisation of acid-induced muscle allodynia in rats.

Previous studies have shown that repeated injections of acidic saline, given into the lateral gastrocnemius muscle of rats, results in a bilateral reduction in withdrawal threshold to tactile stimulation of the hindpaws. We have now characterised this model of muscoskeletal pain pharmacologically, by evaluating the antinociceptive effects of various analgesics after systemic administration. The micro-opioid receptor agonist morphine (3 and 6 mg/kg) produced a particularly prolonged antiallodynic effect. The glutamate receptor antagonists ([8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9,-tetrahydro-1H-pyrrolo[3,2-h]-iso-quinoline-2,3-dione-3-O-(4-hydroxybutyric acid-2-yl)oxime] NS1209 and ketamine (6 and 15 mg/kg, respectively), the KCNQ K(+) channel openers retigabine and flupirtine (10 and 20 mg/kg, respectively) and the Na(+) channel blocker mexiletine (37.5 mg/kg) also significantly increased paw withdrawal threshold, although to a lesser degree than morphine. In contrast, the anticonvulsant lamotrigine (30 mg/kg), the cyclooxygenase-2 inhibitor carprofen (15 mg/kg) and the benzodiazepine diazepam (3 mg/kg) were ineffective. All antinociceptive effects were observed at nonataxic doses as determined by the rotarod test. These results suggest that in this model, muscle-mediated pain can be alleviated by various analgesics with differing mechanisms of action, and that once established ongoing inflammation does not appear to contribute to this process.

A comparison of the anti-nociceptive effects of voltage-activated Na+ channel blockers in the formalin test.

We have used the rat formalin test to compare the anti-nociceptive properties of several voltage-activated Na(+) channel blockers. The antiarrhthymic mexiletine (37.5 and 50 mg/kg, i.p.) attenuated flinching behaviour in both first and second phases of the test compared with vehicle (P<0.05). The anti-convulsants lamotrigine (15 and 30 mg/kg, i.p.) and carbamazepine (20 mg/kg, i.p.) also inhibited second phase flinching behaviour compared with vehicle (P<0.05), although phenytoin (up to 40 mg/kg, i.p.) was without effect. Riluzole (5 mg/kg, i.p.), in contrast to lubeluzole (up to 10 mg/kg, i.p.) also inhibited second phase flinching behaviour compared with vehicle (P<0.05). When tested against an acute thermal nociceptive stimulus mexiletine, lubeluzole and riluzole exhibited anti-nociceptive effects. The anti-nociceptive doses used in the formalin test produced no motor impairment in the rotarod test. Thus, voltage-activated Na(+) channel blockers can attenuate nociceptive behaviour in the formalin test, and a specific mechanism of action on Na(+) channel function may be required for this to occur.

A comparison of the antinociceptive effects of voltage-activated Na+ channel blockers in two rat models of neuropathic pain.

The pain-relieving effects of various voltage-activated Na(+) channel blockers have been evaluated in two rat models of neuropathic pain; the photochemically induced nerve injury model (Gazelius) and spared nerve injury model. Lidocaine (up to 40 mg/kg, i.p.) and lamotrigine (up to 60 mg/kg, i.p.) had no effect on mechanical or cold allodynia in either model. However, lamotrigine (10, 30 and 60 mg/kg) significantly attenuated mechanical hyperalgesia in the spared nerve injury model, while mexiletine (25 and 37.5 mg/kg, i.p.) attenuated mechanical allodynia in the Gazelius model. Tocainide (50, 75 and 100 mg/kg, i.p.) significantly reduced all types of pain behaviour measured. The present results show that these voltage-activated Na(+) channel blockers have broadly similar antinociceptive effects in these two models of neuropathic pain. They also show that these drugs can have markedly different effects on distinct neuropathic pain-related behaviours within models.

Amygdala GABA-A receptor involvement in mediating sensory-discriminative and affective-motivational pain responses in a rat model of peripheral nerve injury.

The contribution of the amygdala to neuropathic pain processing in animals has not been clearly acknowledged. To assess the relative contribution of amygdala GABA-A receptors in mediating sensory-discriminative and affective-motivational pain components, the GABA-A receptor agonist muscimol and the antagonist bicuculline (both 10-25 ng/microl) were administered by acute bilateral injection directly into the central amygdala in rats with a chronic constriction injury (CCI). Escape/avoidance behaviour reflecting the affective-motivational dimension of pain was measured using a light/dark chamber in combination with suprathreshold nociceptive stimulation, and was defined as a shift from the 'non-aversive' dark area of the chamber to the 'aversive' light area. Hindpaw mechanical allodynia and mechanical hyperalgesia thresholds reflecting the sensory-discriminative dimension of pain were determined prior to and following escape/avoidance testing. Muscimol administration into the amygdala attenuated escape/avoidance behaviour and reversed hindpaw mechanical hypersensitivity in CCI rats; the magnitude of reduction in escape/avoidance behaviour was 2- to 3-fold greater than mechanical allodynia. Surprisingly, administration of bicuculline also attenuated escape/avoidance behaviour but had no effect on nociceptive behaviours. The muscimol-induced reversal of hindpaw mechanical hypersensitivity was completely blocked by co-administration of bicuculline, in contrast to escape/avoidance behaviour. Motility behaviour was unaffected by injection of either drug as determined in the open field test. Thus, amygdala GABA-A receptors appear to play an important role in sensory and especially affective pain processing in neuropathic rats. Furthermore, after nerve injury reflex nociceptive behaviours appear to be under tonic control by descending inputs, which originate from or are modulated within the amygdala.

Hypothalamo-pituitary-adrenal axis dysfunction as a contributory factor to chronic pain and depression.

Chronic pain and depressive illness are variably resistant to treatment with current pharmacologic therapies. Pain as a reflex sensory response is accompanied by a fast autonomic and delayed neuroendocrine response mediated by the sympathoadrenal and hypothalamo-pituitary-adrenal (HPA) axis, respectively. The emotional aspect of the pain response is encoded by corticolimbic systems (including the HPA axis) to encapsulate the relationship between pain, memory, and mood. These same systems contribute to the symptomatology of depression, a common symptom of which is pain. Conversely, many chronic pain patients may suffer from depressive illness, which appears to develop as a consequence of chronic pain. A comparison of key changes in HPA function after chronic stress in animals with clinical depression in humans, reveals some striking similarities. In this article, the role of the HPA axis in the etiology of chronic pain and depression is discussed.

Involvement and role of the hypothalamo-pituitary-adrenal (HPA) stress axis in animal models of chronic pain and inflammation.

Hypothalamo-pituitary-adrenal (HPA) axis changes have been reported in several disease states, including major depressive disorder, rheumatoid arthritis, multiple sclerosis and various other conditions associated with chronic pain. These observations suggest that stress and the HPA axis may play important roles in the pathology of these diseases. In order to contribute to a better understanding of the role that chronic stress may play in human pathology, this review article explores the involvement of the HPA axis in those animal models of chronic pain and inflammation that entail persistent rather than intermittent stress.