Articles: hyperalgesia.
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Intraplantar injection of bee venom (BV) produces persistent spontaneous nociception (PSN), hyperalgesia, and inflammatory swelling of the injected paw. The present study was designed to determine the roles of peripheral metabotropic glutamate receptors (mGluRs) in BV-induced nociception and inflammation. We determined the effects of the group I mGluR antagonist AIDA, the group II mGluR agonist ADPC, and the group III mGluR agonist L-AP4 on BV-induced PSN, mechanical hyperalgesia, and inflammatory swelling. Pretreatment with intraplantar injections of AIDA, ADPC or L-AP4 at different doses significantly inhibited BV-induced PSN over the 1-hour observational period. The inhibitory effects of ADPC and L-AP4 were completely abolished by pretreatment with the group II mGluR antagonist LY341495 and the group III mGluR antagonist MSOP, respectively. Pretreatment with ADPC prevented the BV-induced decrease in paw-withdrawal mechanical threshold (PWMT) in a dose-dependent manner, while pretreatment with AIDA or L-AP4 had no effect. The antihyperalgesic effect of ADPC was completely abolished by pretreatment with LY341495. Pretreatment with AIDA, ADPC or L-AP4 at different doses had no effect on the BV-induced increase in the paw volume (PV), a measurement of inflammatory swelling. All contralateral drug treatments at the highest doses had no effect on BV-induced PSN, decreases in PWMT or increases in PV, eliminating the possibility of drug-induced systemic effects. These data suggest that the activation of mGluRs in the periphery may play a differential role in BV-induced nociception and inflammation. ⋯ The present study demonstrated that the intraplantar injection of antagonists or agonists of different mGluRs produced differential effects on bee venom-induced persistent spontaneous nociception and mechanical hyperalgesia. However, no effects on inflammation were observed, suggesting that mGluRs in the periphery have differential roles. Thus, therapies specifically targeting metabotropic glutamate receptors may improve the treatment of patients with persistent spontaneous nociception and hyperalgesia.
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Nicotinic acetylcholine receptors (nAChRs) are longstanding targets for a next generation of pain therapeutics, but the nAChR subtypes that govern analgesia remain unknown. We tested a series of nicotinic agonists, including many molecules used or tried clinically, on a panel of cloned neuronal nAChRs for potency and selectivity using patch-clamp electrophysiology and a live cell-based fluorescence assay. Nonselective nicotinic agonists as well as compounds selective either for alpha4beta2 or for alpha7 nAChRs were then tested in the formalin and complete Freund's adjuvant models of pain. ⋯ Neither selective nor nonselective alpha7 nicotinic agonists affected the release of pro-inflammatory cytokines in response to antigen challenge. Electrophysiological recordings from spinal cord slice showed a strong nicotine-induced increase in inhibitory synaptic transmission that was mediated partially by alpha4beta2 and only minimally by alpha7 subtypes. Taken with previous studies, the results suggest that agonism of alpha4beta2 nAChRs is necessary but not sufficient to produce analgesia, and that the spinal cord is a key site where the molecular action of nAChRs produces analgesia.
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The objective of this study was to estimate and contrast the occurrence of ictal and interictal cutaneous allodynia (CA) in individuals with migraine with and without temporomandibular disorders (TMD). Both TMD and CA are common in migraine and may be associated with migraine transformation from episodic into a chronic form. Herein we hypothesize that TMD contributes to the development of CA and to more severe headaches. ⋯ TMDs were also associated with change in extra-cephalic pain thresholds. In logistical regression, TMD remained associated with CA after adjusting for aura, gender and age. TMD and CA are associated in individuals with migraine.
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The role of peroxynitrite (PN) as a mediator of nociceptive signaling is emerging. We recently reported that the development of central sensitization that follows the intraplantar injection of carrageenan in rats is associated with spinal PN synthesis. We now demonstrate that a significant pathway through which spinal PN modulates central sensitization is post-translational tyrosine nitration of key proteins involved in the glutamatergic pathway, namely glutamate transporter GLT-1 and glutamine synthetase (GS). ⋯ Carrageenan-induced hyperalgesia was also associated with nitration and inactivation of spinal mitochondrial superoxide dismutase (MnSOD) known to provide a critical source of PN during central sensitization. Nitration of GLT-1 and GS contributes to central sensitization by enhancing glutamatergic neurotransmission. Our results support the critical role of nitroxidative stress in the development of hyperalgesia and suggest that post-translational nitration of enzymes and transporters linked to glutamatergic neurotransmission represent a novel mechanism of central sensitization.
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This study was performed to determine whether spinal GABAergic systems mediate the relieving effects of low frequency electroacupuncture (EA) on cold allodynia in a rat tail model of neuropathic pain. For neuropathic surgery, the right superior caudal trunk was resected at the level between the S1 and S2 spinal nerves innervating the tail. Two weeks after the nerve injury, the intrathecal catheter was implanted. ⋯ EA stimulation at ST36 significantly inhibited the cold allodynia sign, whereas EA at non-acupoint and plain acupuncture at ST36 (without electrical stimulation) did not show antiallodynic effects. Intrathecal administration of gabazine or saclofen blocked the relieving effects of ST36 EA stimulation on cold allodynia. These results suggest that spinal GABA(A) and GABA(B) receptors mediate the suppressive effect of low frequency EA on cold allodynia in the tail neuropathic rats.