Articles: hyperalgesia.
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Previous studies indicate that descending modulation of nociception is progressively increased following persistent inflammation. The present study was designed to further examine the role of supraspinal neurons in descending modulation following persistent inflammation. Constant levels of paw withdrawal (PW) and tail flick (TF) latencies to noxious heat stimuli were achieved in lightly anesthetized rats (pentobarbital sodium 3-10 mg/kg/h, i.v.). ⋯ Compared to vehicle-injected animals, microinjection of a soma-selective excitotoxin, ibotenic acid, enhanced ES-produced inhibition at 3 h but not at 24 h after inflammation. We propose that these time course changes reflect dynamic alterations in concomitant descending facilitation and inhibition. At early time points, NMDA receptor and NGC activation enhance descending facilitation; as time progresses, the dose-response curve of NMDA shifts to the left and descending inhibition dominates and masks any descending facilitation.
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The effects of intrathecal (i.t.) administration of prostaglandin E2 (PGE2) and prostaglandin F2 (PGF2) on behavioral and spinal neuronal responses to mechanical and thermal stimuli were examined in rats. i.t. Administration of either PGE2 (1-100 nmol) or PGF2 (1-100 nmol) produced a robust, dose-dependent mechanical hyperalgesia, but only a weak thermal hyperalgesia and touch-evoked allodynia. Spinal administration of either PGE2 (100 pmol-100 nmol) or PGF2 (1-100 nmol) produced dose-dependent increases in responses of nociceptive specific (NS) neurons to mechanical stimuli, but only modest increases in wide dynamic range (WDR) neurons to mechanical stimuli. ⋯ Both PGE2 and PGF2 produced increases in background discharges of WDR and NS neurons, although this effect was most consistently observed with WDR neurons and PGE2. These behavioral and electrophysiological data suggest that mechanical hyperalgesia induced by spinal administration of PGE2 and PGF2 is mediated mainly by changes in NS neurons. The weak thermal hyperalgesia may reflect changes in WDR neurons.
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Cannabinoids have previously been shown to possess analgesic properties in a model of visceral hyperalgesia in which the neurotrophin, nerve growth factor (NGF), plays a pivotal role. The purpose of this study was to investigate the antihyperalgesic effects of two cannabinoids in NGF-evoked visceral hyperalgesia in order to test the hypothesis that endocannabinoids may modulate the NGF-driven elements of inflammatory hyperalgesia. Intra-vesical installation of NGF replicates many features of visceral hyperalgesia, including a bladder hyper-reflexia and increased expression of the immediate early gene c fos in the spinal cord. ⋯ However, neither CB1 nor CB2 receptor antagonists altered the action of anandamide. PEA-induced reduction in Fos expression was abrogated by SR144528. These data add to the growing evidence of a therapeutic potential for cannabinoids, and support the hypothesis that the endogenous cannabinoid system modulates the NGF-mediated components of inflammatory processes.
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Metabotropic glutamate receptor 5 (mGluR5) protein increased after sciatic nerve section in ipsilateral L4 and L5 DRG neuronal profiles, with most of the increase occurring in myelinated A-fiber somata. mGluR5 also increased in lamina II of the ipsilateral spinal cord and the proximal sciatic nerve stump in this model. After L5 spinal nerve ligation, mGluR5 immunoreactivity increased dramatically not only in damaged L5 but also in the neighboring undamaged L4. Interestingly, after partial sciatic nerve section, mGluR5 expression did not change in either L4 or L5 DRG neuronal profiles. ⋯ Furthermore, A-fibers in the uninjured L4 DRG after L5 spinal nerve ligation that have increased mGluR5 are the same A-fibers that newly express vanilloid receptor 1 after such injury. Together, these results suggest that, after L5 spinal nerve injury, mGluR5 expression on A-fibers is essential to the development of thermal hyperalgesia. After partial nerve section, however, it is unlikely that thermal responses are mediated through mGluR5 because no such increase in mGluR5 is detected in this model and MPEP is ineffective.
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Inflammation induces an up-regulation of neuropeptide tyrosine (NPY) and its receptors in the dorsal horn, suggesting an important role in nociceptive transmission. Our initial studies revealed that NPY dose-dependently increased hotplate response latency, and to a lesser degree, thermal paw withdrawal latency (PWL); these effects occurred at doses that affect neither motor coordination (as assessed by the rotarod test) nor paw skin temperature. We next evaluated the behavioral effects of intrathecal administration of NPY and NPY antagonists with the aim of assessing the contribution of NPY to correlates of persistent nociception associated with the unilateral plantar injection of carrageenan or complete Freund's adjuvant (CFA). ⋯ When administered alone, BIBO 3304 (but not BIIE 0246) slightly decreased thermal PWL on the side ipsilateral (25% change), but not contralateral, to CFA injection; this suggests that inflammation strengthens inhibitory NPY tone. We conclude that spinal Y1 receptors contribute to the inhibitory effects of NPY on thermal hypersensitivity in the awake rat. Further studies are necessary to determine whether enhanced release of NPY and Y1-mediated inhibition of spinal nociceptive transmission ultimately results in a compensatory, adaptive inhibition of thermal hypersensitivity in the setting of inflammation.