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In humans, spinal cord lesions induce not only major motor and neurovegetative deficits but also severe neuropathic pain which is mostly resistant to classical analgesics. Better treatments can be expected from precise characterization of underlying physiopathological mechanisms. This led us to thoroughly investigate (i) mechanical and thermal sensory alterations, (ii) responses to acute treatments with drugs having patent or potential anti-allodynic properties and (iii) the spinal/ganglion expression of transcripts encoding markers of neuronal injury, microglia and astrocyte activation in rats that underwent complete spinal cord transection (SCT). SCT was performed at thoracic T8-T9 level under deep isoflurane anaesthesia, and SCT rats were examined for up to two months post surgery. SCT induced a marked hyper-reflexia at hindpaws and strong mechanical and cold allodynia in a limited (6 cm2) cutaneous territory just rostral to the lesion site. At this level, pressure threshold value to trigger nocifensive reactions to locally applied von Frey filaments was 100-fold lower in SCT- versus sham-operated rats. A marked up-regulation of mRNAs encoding ATF3 (neuronal injury) and glial activation markers (OX-42, GFAP, P2×4, P2×7, TLR4) was observed in spinal cord and/or dorsal root ganglia at T6-T11 levels from day 2 up to day 60 post surgery. Transcripts encoding the proinflammatory cytokines IL-1β, IL-6 and TNF-α were also markedly but differentially up-regulated at T6-T11 levels in SCT rats. Acute treatment with ketamine (50 mg/kg i.p.), morphine (3-10 mg/kg s.c.) and tapentadol (10-20 mg/kg i.p.) significantly increased pressure threshold to trigger nocifensive reaction in the von Frey filaments test, whereas amitriptyline, pregabalin, gabapentin and clonazepam were ineffective. Because all SCT rats developed long lasting, reproducible and stable allodynia, which could be alleviated by drugs effective in humans, thoracic cord transection might be a reliable model for testing innovative therapies aimed at reducing spinal cord lesion-induced central neuropathic pain.

Previous data showed that neuropathic pain induced by mechanical lesion of peripheral nerves has specific characteristics and responds differently to alleviating drugs at cephalic versus extracephalic level. This is especially true for tricyclic antidepressants currently used for alleviating neuropathic pain in humans which are less effective against cephalic neuropathic pain. Whether this also applies to the antidepressant agomelatine, with its unique pharmacological properties as MT1/MT2 melatonin receptor agonist and 5-HT2B/5-HT2C serotonin receptor antagonist, has been investigated in two rat models of neuropathic pain. Acute treatments were performed 2 weeks after unilateral chronic constriction (ligation) injury to the sciatic nerve (CCI-SN) or the infraorbital nerve (CCI-ION), when maximal mechanical allodynia had developed in ipsilateral hindpaw or vibrissal pad, respectively, in Sprague–Dawley male rats. Although agomelatine (45 mg/kg i.p.) alone was inactive, co-treatment with gabapentin, at an essentially ineffective dose (50 mg/kg i.p.) on its own, produced marked anti-allodynic effects, especially in CCI-ION rats. In both CCI-SN and CCI-ION models, suppression of mechanical allodynia by ‘agomelatine + gabapentin’ could be partially mimicked by the combination of 5-HT2C antagonist (SB 242084) + gabapentin, but not by melatonin or 5-HT2B antagonist (RS 127445, LY 266097), alone or combined with gabapentin. In contrast, pretreatment by idazoxan, propranolol or the β2 antagonist ICI 118551 markedly inhibited the anti-allodynic effect of ‘agomelatine + gabapentin’ in both CCI-SN and CCI-ION rats, whereas pretreatment by the MT1/MT2 receptor antagonist S22153 was inactive. Altogether these data indicate that ‘agomelatine + gabapentin’ is a potent anti-allodynic combination at both cephalic and extra-cephalic levels, whose action implicates α2- and β2-adrenoreceptor-mediated noradrenergic neurotransmission.

Trigeminal neuropathic pain represents a real challenge to therapy because commonly used drugs are devoid of real beneficial effect or patients frequently become intolerant or refractory to some of these compounds. In a rat model of trigeminal neuropathic pain, which shares numerous similarities with human trigeminal neuralgia and trigeminal neuropathic pain, we used a genomic herpes simplex virus-derived vector (HSVLatEnk) to examine the possible effect of a local overproduction of proenkephalin A (PA) targeted to the trigeminal primary sensory neurons. Unilateral peripheral inoculation of recombinant vectors on the vibrissal pad territory resulted in an about ninefold increase in proenkephalin A mRNA levels in trigeminal ganglion ipsilateral to the infected side. Transgene-derived met-enkephalin accumulated in numerous nerve cell bodies of trigeminal ganglion and was transported through the sensory nerve fibers located in the infraorbital nerve. Bilateral mechanical hyperresponsiveness, which developed 2 weeks after chronic constrictive injury of the left infraorbital nerve, was significantly attenuated in animals overproducing PA in the trigeminal ganglion ipsilateral to the lesioned infraorbital nerve. This antiallodynic effect was reversed by both the opioid receptor antagonist naloxone and the peripherally acting antagonist naloxone methiodide. Our data demonstrate that the local overproduction of PA-derived peptides in trigeminal ganglion sensory neurons evoked a potent antiallodynic effect through the stimulation of mainly peripherally located opioid receptors and suggest that targeted delivery of endogenous opioids may be of interest for the treatment of some severe forms of neuropathic pain.

The functional significance of proenkephalin systems in processing pain remains an open question and indeed is puzzling. For example, a noxious mechanical stimulus does not alter the release of Met-enkephalin-like material (MELM) from segments of the spinal cord related to the stimulated area of the body, but does increase its release from other segments. Here we show that, in the rat, a noxious mechanical stimulus applied to either the right or the left hind paw elicits a marked increase of MELM release during perifusion of either the whole spinal cord or the cervico-trigeminal area. However, these stimulatory effects were not additive and indeed, disappeared completely when the right and left paws were stimulated simultaneously. We have concluded that in addition to the concept of a diffuse control of the transmission of nociceptive signals through the dorsal horn, there is a diffuse control of the modulation of this transmission. The \"freezing\" of Met-enkephalinergic functions represents a potential source of central sensitization in the spinal cord, notably in clinical situations involving multiple painful foci, e.g. cancer with metastases, poly-traumatism or rheumatoid arthritis.

Previous studies suggest that brain opioid activity decreases aggression in animal models. The main objective of the current study was to examine the possible genetic relationship between intermale aggression and brain levels of enkephalins, endorphins, and dynorphins in 11 inbred strains of mice. Pursuit, rattling, and attack behaviors were observed in a dyadic encounter with a standard opponent. It appeared that, as expected, enkephalins and endorphins were always negatively correlated with aggression scores. The findings indicate that brain Met5-enkephalin levels were significantly and highly positively correlated with attack latency. Brain adrenocorticotrophic hormone (ACTH) and beta-endorphin levels were significantly and negatively correlated with the number of rattlings, which is consistent with the hypothesis that rattling is a stress-related behavior. In contrast with Met5-enkephalin, ACTH and beta-endorphin, the correlations between dynorphin A and aggression scores were nonsignificant and very low. These preliminary results suggest that common genetic sources of variation contribute to differences between the 11 inbred strains in both endogenous opioidergic systems and intermale aggression. Further studies are required to confirm the genetic relationship between offensive aggression and brain enkephalins and endorphins and to better understand the mechanisms underlying the role of endogenous opioids in offensive aggression with regard to opioid receptor activity.

Antidepressants, prescribed as first line treatment of neuropathic pain, have a limited efficacy and poorly tolerated side effects. Because recent studies pointed out the implication of astroglial connexins (Cx) in both neuropathic pain and antidepressive treatment, we investigated whether their blockade by mefloquine could modulate the action of the tricyclic antidepressant amitriptyline. Using primary cultures, we found that both mefloquine and amitriptyline inhibited Cx43-containing gap junctions, and that the drug combination acted synergically. We then investigated whether mefloquine could enhance amitriptyline efficacy in a preclinical model of neuropathic pain. Sprague-Dawley rats that underwent chronic unilateral constriction injury (CCI) to the sciatic nerve (SN) were treated with either amitriptyline, mefloquine or the combination of both drugs. Whereas acute treatments were ineffective, chronic administration of amitriptyline reduced CCI-SN-induced hyperalgesia-like behavior, and this effect was markedly enhanced by co-administration of mefloquine, which was inactive on its own. No pharmacokinetic interactions between both drugs were observed and CCI-SN-induced neuroinflammatory and glial activation markers remained unaffected by these treatments in dorsal root ganglia and spinal cord. Mechanisms downstream of CCI-SN-induced neuroinflammation and glial activation might therefore be targeted. Connexin inhibition in astroglia could represent a promising approach towards improving neuropathic pain therapy by antidepressants.

Previous data showed that neuropathic pain induced by mechanical lesion of peripheral nerves has specific characteristics and responds differently to alleviating drugs at cephalic versus extracephalic level. This is especially true for tricyclic antidepressants currently used for alleviating neuropathic pain in humans which are less effective against cephalic neuropathic pain. Whether this also applies to the antidepressant agomelatine, with its unique pharmacological properties as MT /MT melatonin receptor agonist and 5-HT /5-HT serotonin receptor antagonist, has been investigated in two rat models of neuropathic pain. Acute treatments were performed 2 weeks after unilateral chronic constriction (ligation) injury to the sciatic nerve (CCI-SN) or the infraorbital nerve (CCI-ION), when maximal mechanical allodynia had developed in ipsilateral hindpaw or vibrissal pad, respectively, in Sprague-Dawley male rats. Although agomelatine (45 mg/kg i.p.) alone was inactive, co-treatment with gabapentin, at an essentially ineffective dose (50 mg/kg i.p.) on its own, produced marked anti-allodynic effects, especially in CCI-ION rats. In both CCI-SN and CCI-ION models, suppression of mechanical allodynia by 'agomelatine + gabapentin' could be partially mimicked by the combination of 5-HT antagonist (SB 242084) + gabapentin, but not by melatonin or 5-HT antagonist (RS 127445, LY 266097), alone or combined with gabapentin. In contrast, pretreatment by idazoxan, propranolol or the β antagonist ICI 118551 markedly inhibited the anti-allodynic effect of 'agomelatine + gabapentin' in both CCI-SN and CCI-ION rats, whereas pretreatment by the MT /MT receptor antagonist S22153 was inactive. Altogether these data indicate that 'agomelatine + gabapentin' is a potent anti-allodynic combination at both cephalic and extra-cephalic levels, whose action implicates α - and β -adrenoreceptor-mediated noradrenergic neurotransmission.

Peripheral lesion to the trigeminal nerve may induce severe pain states. Several lines of evidence have suggested that the antimigraine effect of the triptans with 5‐HT 1B/1D receptor agonist properties may result from inhibition of nociceptive transmission in the spinal nucleus of the trigeminal nerve by these drugs. On this basis, we have assessed the potential antinociceptive effects of sumatriptan and zolmitriptan, compared to dihydroergotamine (DHE), in a rat model of trigeminal neuropathic pain. Chronic constriction injury was produced by two loose ligatures of the infraorbital nerve on the right side. Responsiveness to von Frey filament stimulation of the vibrissal pad was used to evaluate allodynia. Two weeks after ligatures, rats with a chronic constriction of the right infraorbital nerve displayed bilateral mechanical hyper‐responsiveness to von Frey filament stimulation of the vibrissal pad with a mean threshold of 0.38±0.04 g on the injured side and of 0.43±0.04 g on the contralateral (left) side (versus 12.5 g on both sides in the same rats prior to nerve constriction injury). Sumatriptan at a clinically relevant dose (100 μg kg −1 , s.c.) led to a significant reduction of the mechanical allodynia‐like behaviour on both the injured and the contralateral sides (peak‐effects 6.3±1.1 g and 4.4±0.7 g, respectively). A more pronounced effect was obtained with zolmitriptan (100 μg kg −1 , s.c.) (peak‐effects: 7.4±0.9 g and 3.2±1.3 g) whereas DHE (50–100 μg kg −1 , i.v.) was less active (peak‐effect ∼1.5 g). Subcutaneous pretreatment with the 5‐HT 1B/1D receptor antagonist, GR 127935 (3 mg kg −1 ), prevented the anti‐allodynia‐like effects of triptans and DHE. Pretreatment with the 5‐HT 1A receptor antagonist, WAY 100635 (2 mg kg −1 , s.c.), did not alter the effect of triptans but significantly enhanced that of DHE (peak effect 4.3±0.5 g). In a rat model of peripheral neuropathic pain, which consisted of a unilateral loose constriction of the sciatic nerve, neither sumatriptan (50–300 μg kg −1 ) nor zolmitriptan (50–300 μg kg −1 ) modified the thresholds for paw withdrawal and vocalization in response to noxious mechanical stimulation. These results support the rationale for exploring the clinical efficacy of brain penetrant 5‐HT 1B/1D receptor agonists as analgesics to reduce certain types of trigeminal neuropathic pain in humans. British Journal of Pharmacology (2002) 137 , 1287–1297. doi: 10.1038/sj.bjp.0704979

Peripheral lesion to the trigeminal nerve may induce severe pain states. Several lines of evidence have suggested that the antimigraine effect of the triptans with 5‐HT1B/1D receptor agonist properties may result from inhibition of nociceptive transmission in the spinal nucleus of the trigeminal nerve by these drugs. On this basis, we have assessed the potential antinociceptive effects of sumatriptan and zolmitriptan, compared to dihydroergotamine (DHE), in a rat model of trigeminal neuropathic pain. Chronic constriction injury was produced by two loose ligatures of the infraorbital nerve on the right side. Responsiveness to von Frey filament stimulation of the vibrissal pad was used to evaluate allodynia. Two weeks after ligatures, rats with a chronic constriction of the right infraorbital nerve displayed bilateral mechanical hyper‐responsiveness to von Frey filament stimulation of the vibrissal pad with a mean threshold of 0.38±0.04 g on the injured side and of 0.43±0.04 g on the contralateral (left) side (versus 12.5 g on both sides in the same rats prior to nerve constriction injury). Sumatriptan at a clinically relevant dose (100 μg kg−1, s.c.) led to a significant reduction of the mechanical allodynia‐like behaviour on both the injured and the contralateral sides (peak‐effects 6.3±1.1 g and 4.4±0.7 g, respectively). A more pronounced effect was obtained with zolmitriptan (100 μg kg−1, s.c.) (peak‐effects: 7.4±0.9 g and 3.2±1.3 g) whereas DHE (50–100 μg kg−1, i.v.) was less active (peak‐effect ∼1.5 g). Subcutaneous pretreatment with the 5‐HT1B/1D receptor antagonist, GR 127935 (3 mg kg−1), prevented the anti‐allodynia‐like effects of triptans and DHE. Pretreatment with the 5‐HT1A receptor antagonist, WAY 100635 (2 mg kg−1, s.c.), did not alter the effect of triptans but significantly enhanced that of DHE (peak effect 4.3±0.5 g). In a rat model of peripheral neuropathic pain, which consisted of a unilateral loose constriction of the sciatic nerve, neither sumatriptan (50–300 μg kg−1) nor zolmitriptan (50–300 μg kg−1) modified the thresholds for paw withdrawal and vocalization in response to noxious mechanical stimulation. These results support the rationale for exploring the clinical efficacy of brain penetrant 5‐HT1B/1D receptor agonists as analgesics to reduce certain types of trigeminal neuropathic pain in humans. British Journal of Pharmacology (2002) 137, 1287–1297. doi:10.1038/sj.bjp.0704979

Neuropathic pain is a chronic disease caused by lesion of dysfunction of the central or peripheral nervous system, which affects a midrange estimate of 3% of the general population. It is a major public health problem because available treatments, which have only empirical bases, are of limited efficacy and are most often endowed with poorly tolerated side effects. Animal models are mandatory for better knowledge of underlying physiopathological mechanisms and development of really efficient and better tolerated rational therapies. Clinical observations allowed the design of numerous animal models (mainly in rats and mice), with neuropathic pain‐like symptoms, particularly hyperalgesia and allodynia, which respond to alleviating drugs used in patients such as antidepressants, anticonvulsants and topical anesthetics. This review article describes the in vivo models that consist of peripheral nerve section or ligation, laser‐induced nerve injury, spinal cord lesion, treatments with neurotoxic drugs (notably anticancer and antiretroviral drugs), among others. However, to date, none of these models really mimics human neuropathic pain, especially because the psychoaffective and cognitive components of human pain are difficult to assess using animal models. Recent design of innovative paradigms allowing assessment of not only hyperalgesia and allodynia, but also associated emotional, affective and cognitive dysfunctions might open new avenues for drug discovery, which is particularly needed for neuropathic pain treatment.