Pain
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Cizolirtine (5-9[(N,N-dimethylaminoethoxy)phenyl]methyl0-1-methyl-1H-pyrazol citrate) is a centrally acting analgesic with a currently unknown mechanism of action, whose efficacy has been demonstrated in various models of acute and inflammatory pain in rodents. Further studies were performed in order to assess its potential antinociceptive action in a well-validated model of neuropathic pain, i.e. that produced by unilateral sciatic nerve constriction in rats. Animals were subjected to relevant behavioural tests based on mechanical (vocalization threshold to paw pressure) and thermal (struggle latency to paw immersion in a cold (10 degrees C) water bath) stimuli, 2 weeks after sciatic nerve constriction, when pain-related behaviour was fully developed. ⋯ On the other hand, cizolirtine (10 mg/kg p.o.) produced no motor deficits in animals using the rotarod test. Our study showed that cizolirtine suppressed pain-related behavioural responses to mechanical and cold stimuli in neuropathic rats, probably via an alpha(2)-adrenoceptor-dependent mechanism. These results suggest that cizolirtine may be useful for alleviating some neuropathic somatosensory disorders, in particular cold allodynia, with a reduced risk of undesirable side effects.
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In this study, a new behavioral assessment of craniofacial muscle pain in the lightly anesthetized rat is described. Intramuscular injections with algesic agents in lightly anesthetized rats evoked a characteristic ipsilateral hindpaw shaking behavior for several minutes similar to previously described orofacial pain-induced grooming behavior in awake rats (Neurosci Lett 103 (1989) 349, Pain 62 (1995) 295). Eighty-two male Sprague-Dawley rats were used in a series of experiments to study whether this behavior could serve as a valid measure of craniofacial muscle pain. ⋯ Finally, we showed that systemic administration of morphine sulfate (3 and 0.3 mg/kg, i.p.) dose dependently attenuated mustard oil induced hindpaw-shaking behavior. Lidocaine injected locally 5 min prior to mustard oil injection also significantly decreased the hindpaw shaking behavior. Based on these results we concluded that ipsilateral hindpaw shaking in lightly anesthetized rats is a stereotypical behavior evoked by noxious muscle stimulation and can be used as a reliable behavioral measure to assess craniofacial muscle pain.
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The spinothalamic tract (STT) has been classically viewed as the major ascending pathway for pain transmission while the dorsal column (DC) was thought to be involved primarily in signaling innocuous stimuli. Recent clinical studies have shown that limited midline myelotomy, which transects fibers in the DC, offers good pain relief in patients with visceral cancer pain. Experimental studies provided evidence that a DC lesion decreases the activation of thalamic neurons by visceral stimuli and suggested that this effect is due to transection of the axons of postsynaptic dorsal column (PSDC) neurons. ⋯ Intradermal capsaicin injection also evoked Fos expression in both PSDC and STT neurons, but with no significant difference between these two, when expressed as a percentage of the retrogradely labeled cells (11.6+/-2.9% SEM, 10.8+/-1.1% SEM). These results show that both PSDC and STT neurons are activated by cutaneous and visceral noxious stimuli. Their particular role in transmission and modulation of painful stimuli needs to be investigated further.
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The discovery that the endogenous morphine-like peptides named enkephalins are inactivated by two metallopeptidases, neutral endopeptidase and aminopeptidase N, which can be blocked by dual inhibitors, represents a promising way to develop 'physiological' analgesics devoid of the side effects of morphine. A new series of dual aminophosphinic inhibitors of the two enkephalin-catabolizing enzymes has been recently designed. In this study, one of these inhibitors, RB3007, was tested in various assays commonly used to select analgesics (mouse hot-plate test, rat tail-flick test, writhing and formalin tests in mice, and paw pressure test in rats), and the extracellular levels of the endogenous enkephalins in the ventrolateral periaqueductal grey have been measured by microdialysis after systemic administration of RB3007. ⋯ This increase parallels the antinociceptive responses observed. In addition, strong facilitatory effects of subanalgesic doses of the CCK(2) receptor antagonist, PD-134,308 or the synthetic opioid agonist, methadone on RB3007-induced antinociceptive responses were observed. These findings may constitute promising data for future development of a new class of analgesics that could be of major interest in a number of severe and persistent pain syndromes.
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Cyclooxygenase-2 (COX-2) activity in the spinal cord plays a key role in sensitization to sensory stimuli during acute inflammation. In contrast, intrathecal administration of COX-2 specific inhibitors has minimal analgesic effects in an incisional model of postoperative pain. We investigated the role of COX isoforms in this model by examining the expression of COX-1 and the effect of intrathecal COX inhibitors. ⋯ Ketorolac and SC-560 dose-dependently increased withdrawal threshold in this model, but NS-398 had no effect. These results suggest that COX-1 plays an important role in spinal cord pain processing and sensitization after surgery. Increased COX-1 activity could precede the up-regulation of COX-1 protein, and spinally administered specific COX-1 inhibitors may be useful to treat postoperative pain.