The journal of pain : official journal of the American Pain Society
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Primary headaches such as migraine are postulated to involve the activation of sensory trigeminal pain neurons that innervate intracranial blood vessels and the dura mater. It is suggested that local activation of these sensory nerves may involve dural mast cells as one factor in local inflammation, causing sensitization of meningeal nociceptors. Immunofluorescence was used to study the detailed distribution of calcitonin gene-related peptide (CGRP) and its receptor components calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in whole-mount rat dura mater and in human dural vessels. The relative distributions of CGRP, CLR, and RAMP1 were evaluated with respect to each other and in relationship to mast cells, myelin, substance P, neuronal nitric oxide synthase, pituitary adenylate cyclase-activating polypeptide, and vasoactive intestinal peptide. CGRP expression was found in thin unmyelinated fibers, whereas CLR and RAMP1 were expressed in thicker myelinated fibers coexpressed with an A-fiber marker. CLR and RAMP1 immunoreactivity colocalized with mast cell tryptase in rodent; however, expression of both receptor components was not observed in human mast cells. Immunoreactive substance P fibers coexpressed CGRP, although neuronal nitric oxide synthase and vasoactive intestinal peptide expression was very limited, and these fibers were distinct from the CGRP-positive fibers. Few pituitary adenylate cyclase-activating polypeptide immunoreactive fibers occurred and some colocalized with CGRP. ⋯ This study demonstrates the detailed distribution of CGRP and its receptor in the dura mater. These data suggest that CGRP is expressed in C-fibers and may act on A-fibers, rodent mast cells, and vascular smooth muscle cells that express the CGRP receptor. These sites represent potential pathophysiological targets of novel antimigraine agents such as the newly developed CGRP receptor antagonists.
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Levetiracetam is a novel anticonvulsant with antihyperalgesic efficacy in inflammatory pain. Nonsteroidal analgesics and caffeine, as analgesic adjuvant, are widely used against inflammatory pain. This study characterized the manner in which levetiracetam interacts with analgesics (ibuprofen, celecoxib, and paracetamol) and caffeine to suppress hyperalgesia in a model of localized inflammation. Rat paw inflammation was induced by intraplantar carrageenan (.1 mL, 1%). Hyperalgesia and antihyperalgesic effects of levetiracetam (orally), analgesics (orally), and caffeine (intraperitoneally) alone and 2-drug combinations of levetiracetam with analgesics or caffeine were examined by a modified paw pressure test. The type of interaction between components was determined by isobolographic analysis or by analysis of the log dose-response curves for drug combination and drugs alone. Levetiracetam (10-200 mg/kg), ibuprofen (12.5-100 mg/kg), celecoxib (3.75-30 mg/kg), paracetamol (50-200 mg/kg), caffeine (15-100 mg/kg), and 2-drug combinations of levetiracetam with analgesics/caffeine produced a significant, dose-dependent reduction of inflammatory hyperalgesia. Isobolographic analysis revealed that levetiracetam exerts a synergistic interaction with analgesics, with approximately 7-, 9-, and 11-fold reduction of doses of both drugs in combination of levetiracetam with paracetamol, celecoxib, and ibuprofen, respectively. Analysis of the log dose-response curves for levetiracetam (1-50 mg/kg) in the presence of caffeine (10 mg/kg) and levetiracetam applied alone also revealed a synergistic interaction. Levetiracetam's ED50 in the presence of caffeine was reduced approximately 11-fold. ⋯ The presented data suggest that 2-drug combinations of levetiracetam and nonsteroidal analgesics or caffeine could be useful in treatment of inflammatory pain. The efficacy and the adverse effects of those mixtures should be explored further in clinical settings.
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Endomorphin 2 (EM2) is the predominant endogenous mu-opioid receptor (MOR) ligand in the spinal cord. Given its endogenous presence, antinociceptive responsiveness to the intrathecal application of EM2 most likely reflects its ability to modulate nociception when released in situ. In order to explore the physiological pliability of sex-dependent differences in spinal MOR-mediated antinociception, we investigated the antinociception produced by intrathecal EM2 in male, proestrus female, and diestrus female rats. Antinociception was reflected by changes in tail flick latency to radiant heat. In females, the spinal EM2 antinociceptive system oscillated between analgesically active and inactive states. During diestrus, when circulating estrogens are low, spinal EM2 antinociceptive responsiveness was minimal. In contrast, during proestrus, when circulating estrogens are high, spinal EM2 antinociception was robust and comparable in magnitude to that manifest by males. Furthermore, in proestrus females, spinal EM2 antinociception required spinal dynorphin and kappa-opioid receptor activation, concomitant with MOR activation. This is required for neither spinal EM2 antinociception in males nor the antinociception elicited in proestrus females by spinal sufentanil or [d-Ala(2),N-methyl-Phe(4),Gly-ol(5)]-enkephalin, which are prototypic MOR-selective nonpeptide and peptide agonists, respectively. These results reveal that spinal EM2 antinociception and the signaling mechanisms used to produce it fundamentally differ in males and females. ⋯ The inability to mount spinal EM2 antinociception during defined stages of the estrus (and presumably menstrual) cycle and impaired transition from spinal EM2 analgesically nonresponsive to responsive physiological states could be causally associated with the well-documented greater severity and frequency of chronic intractable pain syndromes in women vs men.
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Randomized Controlled Trial
An explanatory study evaluating the muscle relaxant effects of intramuscular magnesium sulphate for dystonia in complex regional pain syndrome.
The treatment of dystonia related to complex regional pain syndrome (CRPS) remains unsatisfactory, raising the need of alternative targets for intervention. In dystonia, pathologic muscle changes may occur, which contributes to stiffness. Because magnesium sulphate may act as a muscle relaxant through its actions on the neuromuscular junction and muscle, we performed an explanatory study of the muscle relaxant effect and safety of intramuscular magnesium sulphate (IMMG) in CRPS patients with dystonia. In a double-blind randomized placebo-controlled crossover study, 30 patients were assigned to 3-week treatments of IMMG and placebo. Treatments were separated by a 1-week washout period. The daily dose of IMMG was 1,000 mg in week 1, 1,500 mg in week 2, and 2,000 mg in week 3. The primary outcome measure was the difference in change in Burke-Fahn-Marsden scores after 3 weeks of treatment between both interventions. Secondary outcomes involved severity of dystonia, myoclonus, tremor, and pain, and functional activity. Data of 22 patients available for the explanatory analysis revealed no significant differences between IMMG and placebo treatment in any of the outcomes. In conclusion, we found no indication of efficacy of IMMG in a daily dose of 2,000 mg as a muscle relaxant in CRPS-related dystonia. ⋯ In this double-blind placebo-controlled crossover study there was no evidence found of a muscle relaxant effect of intramuscular magnesium sulphate in dystonia related to CRPS. Consequently, there is insufficient support for new studies evaluating the efficacy of other routes of MG administration in CRPS-related dystonia.