The journal of pain : official journal of the American Pain Society
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In this report, we demonstrate the transcription, expression, and DNA-binding properties of the peroxisome proliferator-activated receptor (PPAR)-gamma subtype of the peroxisome proliferator-activated nuclear receptor family to the spinal cord with real-time PCR, Western blot, and electrophoretic mobility shift assay. To test the hypothesis that activation of spinal PPAR-gamma decreases nerve injury-induced allodynia, we intrathecally administered PPAR-gamma agonists and/or antagonists in rats after transection of the tibial and common peroneal branches of the sciatic nerve. Single injection of either a natural (15-deoxy-prostaglandin J2, 15d-PGJ2) or synthetic (rosiglitazone) PPAR-gamma agonist dose-dependently decreased mechanical and cold hypersensitivity. These effects were maximal at a dose of 100 microg and peaked at approximately 60 minutes after injection, a rapid time course suggestive of transcription-independent mechanisms of action. Concurrent administration of a PPAR-gamma antagonist (bisphenol A diglycidyl ether, BADGE) reversed the effects of 15d-PGJ2 and rosiglitazone, further indicating a receptor-mediated effect. In animals without nerve injury, rosiglitazone did not alter motor coordination, von Frey threshold, or withdrawal response to a cool stimulus. Intraperitoneal and intracerebroventricular administration of PPAR-gamma agonists (100 microg) did not decrease mechanical and cold hypersensitivity, arguing against effects subsequent to diffusion from the intrathecal space. We conclude that ligand-induced activation of spinal PPAR-gamma rapidly reverses nerve injury-induced mechanical allodynia. New or currently available drugs targeted at spinal PPAR-gamma may yield important therapeutic effects for the management of neuropathic pain. ⋯ PPAR-gamma receptor agonists such as rosiglitazone and pioglitazone are approved as insulin sensitizers by the United States Food and Drug Administration. We demonstrate PPAR-gamma expression in the spinal cord and report that activation of these receptors inhibits allodynia. BBB-permeant PPAR-gamma agonists may yield important therapeutic effects for the management of neuropathic pain.
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The aim of this study was to investigate the influence of sex and ovarian hormones on formalin- and glutamate-induced temporomandibular joint (TMJ) nociception in rats. The influence of sex and ovarian hormones on the nociceptive behavior induced by formalin or glutamate was virtually the same. The nociceptive behavior of males was similar to that of females in the proestrus phase of the estrous cycle but was significantly lower than that in the diestrus phase. Since the serum level of estradiol but not of progesterone was significantly higher in the proestrus than in the diestrus phase, these data suggest that females with lower endogenous serum level of estradiol have an exacerbation of TMJ nociception. The nociceptive behavior of ovariectomized rats was similar to that of diestrus females and significantly greater than that of proestrus females. Although the administration of estradiol or progesterone in ovariectomized females significantly reduced TMJ nociception, the combination of both hormones did not increase the antinociceptive effect induced by each of them. These findings suggest that estradiol and progesterone decrease TMJ nociception in an independent way. ⋯ We report that ovarian hormones have an antinociceptive effect on the TMJ formalin and glutamate nociceptive behavior models. Therefore, the greater prevalence and severity of TMJ pain in women of reproductive age may be a consequence of hormonal fluctuation during the reproductive cycle, in that during low endogenous estradiol serum level TMJ pain sensitivity is increased, enhancing the risk of females experiencing TMJ pain.
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Chronic pain conditions remain a high unmet medical need, and a significant number of patients are not effectively treated with currently available therapies. There is a significant challenge in developing more effective therapies to treat pain, particularly in chronic debilitating pain conditions such as neuropathic pain. Preclinical research has been beneficial in advancing mechanistic understanding of the pathophysiology of pain as well as in defining new therapeutic targets for intervention. However, the increased understanding of the neurobiology of pain has not yet translated into breakthroughs in pain therapies. Some debate exists as to how predictive the common animal models of pain are to the human condition. Translation animal model activity promises to be enhanced by application of novel neuroimaging technologies. It is well acknowledged throughout the industry that the application of preclinical to clinical translational biomarkers is an important strategy that holds promise in increasing the confidence in the translatability of the preclinical to clinical data. Imaging biomarkers have tremendous potential for affecting pain research from both diagnostic as well as therapeutic standpoints. Noninvasive imaging has the inherent advantage of being able to evaluate central mechanisms of pain and the effects of intervention both in animals and in humans. Because each subject serves as its own control, the inherent intersubject variabilities can be less of a confound. This review discusses both the promise and limitations of using imaging modalities to study pain processing and integrates it into the evolving drug discovery and development paradigm. Each section summarizes current clinical reports and, if applicable, preclinical translational findings. Emphasis is given to technical areas for future development and revealing neuroinflammation dynamics and targets that are influenced by genetics and cellular insults. With continued application of neuroimaging technologies, new therapeutic approaches to treat chronic pain as well as define tools to assess functional outcomes promise to emerge. ⋯ This review discusses the promises and limitations of using noninvasive imaging modalities to study pain processing and integrates it into the evolving drug discovery and development paradigm. Emerging neuroimaging technologies may spawn new therapeutic approaches to treat chronic pain as well as define translational tools to assess functional clinical outcomes.