Pain
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In previous studies, pain behaviors produced in the spinal nerve ligation rat model of neuropathic pain were partly reduced by surgical lumbar sympathectomy. However, systemic injection of phentolamine, an alpha-adrenoceptor blocker, was not effective in reducing pain behaviors, at least in the Sprague-Dawley strain of rats. This suggests that sympathectomy removes not only adrenoceptor function but also other factors that must contribute importantly to the generation of neuropathic pain behaviors. ⋯ This effect was observed in a subset of neuropathic rats, and the drug responses were consistent in repeated treatments within the animal group. Neither phentolamine nor suramin changed the mechanical sensitivity of neuropathic rats when given alone. The data suggest that the purinergic substance ATP is co-released with NE from sympathetic nerve terminals and these two are together involved, at least in part, in the maintenance of the sympathetically dependent component of pain behaviors in some neuropathic rats.
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The present studies assessed the role of G(zalpha) and G(oalpha) in spinal alpha(2) adrenergic receptor agonist-induced antinociception, as well as in antinociceptive synergism between spinal morphine and clonidine. Mice were pretreated with a single intrathecal (i.t.) injection of artificial cerebrospinal fluid (ACSF), antisense oligodeoxynucleotide(s) (ODN) directed against G(zalpha) or G(oalpha), or nonsense ODN. After 48 h, the antinociceptive effects expressed as per cent maximal possible effect (% MPE) of either i.t. morphine alone, clonidine alone or coadministered morphine plus clonidine, were evaluated in the tail flick test. ⋯ Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO)- (mu opioid receptor agonist) and U50-488 (kappa opioid receptor agonist) -induced antinociception. Pretreatment with antisense ODN to G(oalpha) attenuated both morphine and clonidine induced antinociception and did not affect synergism between the agonists. These results suggest that spinal G(o)alpha mediates antinociception produced by both clonidine and morphine while G(zalpha) mediates alpha(2) adrenergic and delta opioid receptor mediated antinociception, but not antinociception produced by mu or kappa opioid agonists.
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We have recently reported that injury to a lumbar root in a rat model of radiculopathy produces spinal glial activation associated with elevated proinflammatory cytokines. Based on our hypothesis that central neuroinflammatory processes may manifest clinically as radicular pain, we undertook pharmacological intervention using the immunosuppressive agent methotrexate (MTX). The L5 lumbar spinal root (central to the dorsal root ganglia) was exposed unilaterally and loosely constricted with chromic gut. ⋯ However, spinal expression of MHC II was markedly reduced in the MTX treated group as compared with the saline treated group. The exact mechanism of action of MTX in attenuating mechanical allodynia has not yet been elucidated. The present results indicate that MTX administration may offer a new treatment modality for radicular pain with or without disc herniation as well as directing new research into the development of novel immunomodulators for the treatment of chronic neuropathic and radicular pain.
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Peripheral neuropathic pain is produced by multiple etiological factors that initiate a number of diverse mechanisms operating at different sites and at different times and expressed both within, and across different disease states. Unraveling the mechanisms involved requires laboratory animal models that replicate as far as possible, the different pathophysiological changes present in patients. It is unlikely that a single animal model will include the full range of neuropathic pain mechanisms. ⋯ The mechanical (von Frey and pinprick) sensitivity and thermal (hot and cold) responsiveness is increased in the ipsilateral sural and to a lesser extent saphenous territories, without any change in heat thermal thresholds. Crush injury of the tibial and common peroneal nerves produce similar early changes, which return, however to baseline at 7-9 weeks. The spared nerve injury model may provide, therefore, an additional resource for unraveling the mechanisms responsible for the production of neuropathic pain.
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Mechanical allodynia- and hyperalgesia-like behavior which develops in rats after L5 spinal nerve lesion has been suggested to be due to ectopic activity in the lesioned afferent neurons originating at the lesion site and/or in the dorsal root ganglion because it is eliminated by section of the dorsal root. Here we reevaluated the effect of a dorsal rhizotomy in rats after L5 spinal nerve lesion. Using calibrated von Frey hairs, paw withdrawal threshold to single stimuli and paw withdrawal incidence to repetitive stimulation were tested before and after nerve section. ⋯ These results challenge the widely accepted idea that neuropathic pain behavior developing after spinal nerve lesion is dependent on ectopic activity in the lesioned afferent neurons. However, the present results do not rule out the possibility that after the two nerve lesions the mechanisms generating neuropathic pain behavior are different. After dorsal rhizotomy neuropathic pain behavior may be related to deafferentation whereas after spinal nerve lesion it may be caused by ectopic activity.