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Antidepressants remain one of the first line treatments prescribed to neuropathic pain patients despite their limited efficacy and/or their numerous side effects. More and more, pharmacotherapy for neuropathic pain has evolved towards the use of therapeutic combinations. The goal of the present study was to assess the efficacy of the combination of antidepressants - selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors-with a peptide (TAT-2ASCV) able to disrupt the interaction between serotonin type 2A (5-HT

N-methyl-D-aspartate receptor (NMDAR) antagonists may be given in persistent neuropathic pain, but adverse events especially with ketamine may limit their clinical use. Less central and cognitive adverse events are described with dextromethorphan and memantine. These molecules have been explored in many preclinical and clinical studies, but data are conflicting as regards neuropathic pain alleviation. Dextromethorphan and memantine have been administered to animals after spinal nerve ligation (SNL) to evaluate their antinociceptive/cognitive effects and associated molecular events, including the phosphorylation of several tyrosine (pTyr(1336), pTyr(1472)) residues in the NR2B NMDAR subunit. Spinal nerve ligation and sham animals received dextromethorphan (10 mg/kg, i.p.), memantine (20 mg/kg, i.p.) or saline (1 mL/kg, i.p.). These drugs were administered once symptoms of allodynia and hyperalgesia had developed. Tests were carried out before and after surgery. Tactile allodynia, mechanical hyperalgesia and spatial memory were, respectively, evaluated by von Frey, Randall & Selitto and Y-maze tests and molecular events by Western blot analysis. Spinal nerve-ligated animals displayed nociception and impaired spatial memory. Dextromethorphan, but not memantine, reversed neuropathic pain (NP) symptoms, restored spatial memory integrity and decreased the expression of pTyr(1336)NR2B. Following postoperative administration of dextromethorphan, this study has demonstrated for the first time a concordance between behaviour, cognitive function and molecular events via pTyr(1336)NR2B for neuropathic pain alleviation. Confirmation of these findings in patients would constitute a major step forward in the treatment of neuropathic pain and in the improvement of cognitive function and quality of life.

N-methyl-D-aspartate (NMDA) receptor antagonists are used for post-surgery neuropathic pain but severe side-effects limit their clinical use. Memantine, when given after surgery, shows conflicting results as regard to neuropathic pain alleviation. Here memantine is administered in animals before or after spinal nerve ligation (SNL) in order to evaluate the induced antinociceptive/cognitive effects and associated molecular events, including the phosphorylation of several tyrosine (pTyr(1336), pTyr(1472)) and serine (pSer(1303)) residues in the NR2B subunit of the NMDA receptor. Spinal nerve ligated and sham animals received memantine (20mg/kg/day) or vehicle (1ml/kg/day) by intraperitoneal route. Pre-emptive protocol started 4 days before surgery and continued for 2 days post-surgery. In the post-operative protocol, the 7 day-treatment began on the day of surgery. Tests were done before and after surgery. Tactile allodynia, mechanical hyperalgesia and spatial memory were evaluated by von Frey, Randall & Selitto and Y-maze-tests respectively, and molecular events by western-blot analysis. Spinal nerve ligated animals displayed nociception, impaired memory and increased expression of the 3 phosphorylated residues. Post-operative memantine had no beneficial effect. Pre-emptive memantine prevented the development of post-surgical nociception, impairment of spatial memory and did not increase the expression of pTyr(1472)NR2B at spinal, insular and hippocampal levels. Memantine administered a few days before surgery is a promising strategy to alleviate neuropathic pain development and impairment of cognitive function in animals. The pivotal role of pTyr(1472)NR2B must be studied further, and these findings will now be challenged in patients for the prevention of postsurgical neuropathic pain.

The N-methyl-d-aspartate receptor (NMDAR) contributes to central sensitization in the spinal cord, a phenomenon which comprises various pathophysiological mechanisms responsible for neuropathic pain-like signs in animal models. NMDAR function is modulated by post-translational modifications including phosphorylation, and this is proposed to underlie its involvement in the production of pain hypersensitivity. As in diabetic patients, streptozotocin-induced diabetic rats exhibit or not somatic mechanical hyperalgesia; these rats were named DH and DNH respectively. At three weeks of diabetes, we present evidence that somatic mechanical hyperalgesia was correlated with an enhanced phosphorylation of the NMDAR NR1 subunit (pNR1) in the rat spinal cord. This increase was not found in normal and DNH rats, suggesting that this regulation was specific to hyperalgesia. Double immunofluorescence studies revealed that the numbers of pNR1-immunoreactive neurons and microglial cells were significantly increased in all laminae (I-II and III-VI) of the dorsal horn from DH animals. Western-blots analysis showed no change in NR1 protein levels, whatever the behavioural and glycemic status of the animals. Chronic intrathecal treatment (5μg/rat/day for 7days) by U0126 and MK801, which blocked MEK (an upstream kinase of extracellular signal-regulated protein kinase: ERK) and the NMDAR respectively, simultaneously suppressed somatic mechanical hyperalgesia developed by diabetic rats and decreased pNR1. These results indicate for the first time that increased expression of pNR1 is regulated by ERK and the NMDAR via a feedforward mechanism in spinal neurons and microglia and represents one mechanism involved in central sensitization and somatic mechanical hyperalgesia after diabetes.

Summary— The purpose of this study was to compare the analgesic effect of acute injections (1.25 and 20 mg/kg, ip) of several anti-depressants with different effects on monoamine reuptake, on two pain tests in mice (hot-plate and phenylbenzoquinone-induced abdominal writhes). Serotonergic inhibitors (citalopram, fluvoxamine and clomipramine) were more effective in the hot-plate test whereas noradrenaline reuptake inhibitors (desipramine and maprotilline) were more effective in the writhing test. The mixed antidepressants (amitriptyline and to a lesser degree trimipramine) were more effective in the two tests than the other antidepressant drugs. Changes in motor activity of clomipramine and amitriptyline could not account for the modifications of pain threshold. Amineptine (a dopamine reuptake inhibitor) failed to induce any antinociceptive effect in the hot-plate test and was hyperalgesic in the writhing test, which could be explained by an increased motor activity. These findings indicate that the antinociceptive potency of reuptake inhibitors varies according to their monoamine specificity and the nature of stimuli. They would suggest that the preferential choice of serotonergic antidepressants in the management of chronic pain is arguable.

Agmatine, an endogenous cationic amine resulting from the decarboxylation of L-arginine, produces antihyperalgesic and antiallodynic effects in animal models of chronic neuropathic and inflammatory pain. We examined the effect of agmatine on tactile and thermal allodynia and on mechanical hyperalgesia in streptozocin-induced diabetic rats. To determine its mechanism of action and the potential interest of some of its combinations, the antihyperalgesic effect of agmatine was challenged with alpha(2)-adrenergic imidazoline and opioid-receptor antagonists, and its interaction with the opioid-receptor agonist morphine, the competitive N-methyl-D-aspartate receptor antagonist D-CPP [R(-)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid], and the nitric-oxide synthase inhibitor L-NAME (L-N(G)-nitro-L-arginine methyl ester) were examined. When intrathecally (i.t.) injected (4.4 to 438 nmol/rat), agmatine was ineffective in normal rats but suppressed tactile allodynia (von Frey hair test), thermal allodynia (tail immersion test), and mechanical hyperalgesia (paw-pressure test) in diabetic rats. This spinal antihyperalgesic effect was suppressed by idazoxan (40 micromol/rat i.t.) but not by yohimbine (40 micromol/rat i.t.) or naloxone (0.69 micromol/rat i.v.). In diabetic rats, an isobolographic analysis showed that combinations of i.t. agmatine with i.v. L-NAME or with i.t. morphine resulted in an additive antihyperalgesic effect, whereas the agmatine/D-CPP i.t. combination was superadditive. In summary, the present findings reveal that spinal agmatine produces antiallodynic and antihyperalgesic effects in diabetic neuropathic pain involving, at least for its antihyperalgesic effect, the imidazoline receptors. Moreover, agmatine combined with D-CPP produces an antinociceptive synergy in experimental neuropathy, opening opportunities in the development of new strategies for pain therapy.

The synthesis and the pharmacological evaluation of 19 new 4,6-diaryl-3-pyridazinones are reported. All compounds were screened for analgesic, antiinflammatory and antipyretic activities. Introduction of an arylpiperazinomethyl moiety in the 2-position of the pyridazinone ring resulted in the most potent activities. Compounds 2a, 2b, 2h and 2i exhibited a higher analgesic activity than did aspirin or noramidopyrine in the hot plate test.