Pain
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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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Alterations in activation of pain modulation systems may play a role in the pathophysiology of irritable bowel syndrome (IBS). However, little is known about the effects of exogenous opioids on the perceptual and autonomic responses to aversive visceral stimulation. The aim of the study was to evaluate the effect of the mu opioid-preferring analgesic fentanyl (FEN), given intravenously, on perceptual and autonomic responses to rectal distension. ⋯ FEN had no effect on rectal tone or compliance. FEN dose-dependently attenuates the perception of phasic rectal distension and affects unpleasantness ratings during random fixed rectal distension, with a greater relative efficacy for this antinociceptive effect in IBS patients. These findings support the hypothesis that IBS patients may have an altered central release of endogenous opioids in response to visceral stimulation.
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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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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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Many lines of evidence implicate the somatosensory areas near the lateral sulcus (Sylvian fissure) in the cortical representation of pain. Anatomical tracing studies in the monkey show nociceptive projection pathways to the vicinity of the secondary somatosensory cortex in the parietal operculum, and to anterior parts of insular cortex deep inside the Sylvian fissure. Clinical observations demonstrate alterations in pain sensation following lesions in these two areas in human parasylvian cortex. ⋯ This anatomical separation may be one of the reasons why single unit recordings of nociceptive neurons are scarce within regions comprising low-threshold mechanoreceptive neurons. The functional significance (sensory-discriminative, affective-motivational, cognitive-evaluative) of the closely spaced parasylvian cortical areas in acute and chronic pain is only poorly understood. It is likely that some of these areas are involved in sensory-limbic projection pathways that may subserve the recognition of potentially tissue damaging stimuli as well as pain memory.