A novel method for subarachnoid drug delivery in the medullary region of rats

This study describes a novel method for direct subarachnoid drug delivery to the medullary dorsal horn region of rats, without introducing a catheter. The reliability of the method was demonstrated by a pharmacological validation; that is, morphine administration to the medullary region blocked the nociceptive response to formalin injected in the temporomandibular joint (TMJ) region, an effect that was prevented by co-administration of naloxone. The method proposed offers many advantages over the existing methods for medullary drug delivery with catheter implantation. It is easy to be employed, it does not induce any sign of motor impairment, and it does not require the neck surgery performed to implant a catheter in the medullary dorsal horn region. Therefore, it is a useful method for subarachnoid drug delivery in behavioral trigeminal pain studies, particularly when nociceptive behavioral measures that require normal neck muscle activity to occur, such as head withdraw or head flinch are evaluated. (c) 2005 Elsevier B.V. All rights reserved.148210811

Centralization of noxious stimulus-induced analgesia (NSIA) is related to activity at inhibitory synapses in the spinal cord

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The duration of noxious stimulus-induced antinociception (NSIA) has been shown to outlast the pain stimulus that elicited it, however, the mechanism that determines the duration of analgesia is unknown. We evaluated the role of spinal excitatory and inhibitory receptors (NMDA, mGluR(5), mu-opioid, GABA(A), and GABA(B)), previously implicated in NSIA initiation, in its maintenance. As in our previous studies, the supraspinal trigeminal jaw-opening reflex (JOR) in the rat was used for nociceptive testing because of its remoteness from the region of drug application, the lumbar spinal cord. NSIA was reversed by antagonists for two inhibitory receptors (GABA(B) and mu-opioid) but not by antagonists for either of the two excitatory receptors (NMDA and mGluR(5)), indicating that NSIA is maintained by ongoing activity at inhibitory synapses in the spinal cord. Furthermore, spinal administration of the GABAB agonist baclofen mimicked NSIA in that it could be blocked by prior injection of the p-opioid receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) in nucleus accumbens. CTAP also blocked baclofen antinociception when administered in the spinal cord. We conclude that analgesia induced by noxious stimulation is maintained by activity in spinal inhibitory receptors. (C) 2009 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.1433228232U.S. National Institutes of HealthConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

The protective role of testosterone in the development of temporomandibular joint pain

The lower prevalence of many pain conditions, including temporomandibular dysfunctions, in men than in women has not as yet been clarified. The aim of this study was to investigate the effect of testosterone on the risk of development of temporomanclibular joint (TMJ) pain and on acute persistent TMJ pain. The TMJ formalin test was used as an experimental assay in the rat. Intra-TMJ 0.5% formalin induced a significant nociceptive behavior in naive female rats and gona-dectomized male rats but not in naive male rats, suggesting that naive male rats have a lower risk for development of TMJ pain. The finding that the serum level of testosterone but not of estrogen and progesterone significantly decreased in gonadectomized male rats suggests that testosterone is the hormone underlying the decreased naive male rat's risk for development of TMJ pain. The magnitude of the nociceptive behaviors induced by intra-TMJ 1.5% formalin was similar in gonadectomized and naive male rats. Therefore, in contrast to the protective role of testosterone in TMJ pain development, testosterone, at physiological serum levels, does not appear to modulate acute persistent TMJ pain induced by the TMJ injection of 1.5% formalin. At a supraphysiological serum level, however, testosterone significantly attenuated 1.5% formalin-induced nociception in male rats but not in female rats. This antinociceptive effect was not mediated by estrogen derived from testosterone aromatization, because estrogen administration did not affect 1.5% formalin-induced TMJ nociception in gonadectomized male rats. Perspective: The present findings not only help to explain the lower prevalence of TMJ pain in males versus females but also show that testosterone reduces TMJ pain at supraphysiological serum levels. (c) 2007 by the American Pain Society.8543744

TRPA1-mediated nociception: Response to letter by Reeh

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TRPA1-mediated nociception

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Inhibition of tonic spinal glutamatergic activity induces antinociception in the rat

Inhibition of tonic activity in spino-supraspinal projection neurons induces heterosegmental antinociception that is mediated by opioid receptors in nucleus accumbens. To investigate the origin of this tonic activity, we evaluated the ability of inhibiting neurotransmission in the spinal cord to produce heterosegmental antinociception in the trigeminal nociceptive jaw-opening reflex (JOR) in the rat. Spinal intrathecal administration of calcium channel blockers attenuated the JOR, suggesting that the tonic spinal activity depends on synaptic input. To identify the excitatory neurotransmitter receptors involved, selective antagonists for AMPA/kainate, mGluR(1), NMDA or NK1 receptors were administered intrathecally to the spinal cord. The AMPA/kainate and mGluR(1) receptor antagonists, but not the NMDA or NK1 receptor antagonists, induced antinociception, which was antagonized by intra-accumbens administration of the selective mu-opioid receptor antagonist CTOP. Thus, inhibition of tonic spinal glutamatergic activity resulted in supraspinally mediated antinociception. As this antinociception occurred in the absence of interventions that would produce a facilitated nociceptive state, this tonic glutamatergic activity is important in setting nociceptive threshold.1681547155

The role of transient receptor potential A 1 (TRPA1) in the development and maintenance of carrageenan-induced hyperalgesia

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective cation channel important in setting nociceptive threshold. It is expressed in nociceptive C-fibers and in non-neuronal cells involved in pro-inflammatory mediators' release. We asked whether TRPA1 contributes to carrageenan-induced hyperalgesia in rats, and if so, whether this contribution is mediated by mechanisms involved in inflammation such as cytokine release and neutrophil migration and/or by a direct sensitization of the primary afferent nociceptors. Pharmacological blockade of local TRPA1 by its selective antagonist HC 030031 prevented and reversed carrageenan-induced hyperalgesia, which was detected either by a mechanical or chemical (low dose of capsaicin) stimulus. However, it did not affect either carrageenan-induced cytokines expression or neutrophil migration. The neuronal TRPA1 gene silencing induced by intrathecal pretreatment with antisense oligodoexynucleotide completely prevented carrageenan-induced hyperalgesia over 24 h and significantly reduced TRPA1 expression in the dorsal root ganglia cells (L5-6), which was not affected by carrageenan treatment. We conclude that TRPA1 plays an important role in the development and maintenance of carrageenan-induced inflammatory hyperalgesia by directly contributing to nociceptor excitability. (C) 2012 Elsevier Ltd. All rights reserved.6520621

Peripheral effect of a kappa opioid receptor antagonist on nociception evoked by formalin injected in TMJ of pregnant rats

The effect of sex hormones on orofacial pain modulation is poorly understood. Therefore, this study aimed to investigate the effect of hormonal changes as a result of pregnancy, as well as that of the kappa (kappa) opioid receptor antagonist on female rats' sensitivity to the temporomandibular joint (TMJ) formalin test. Initially, female rats at estrus and pregnant females on day 19 of pregnancy received a 50 mul formalin (1.5%) injection in the right TMJ. The pregnant females showed a reduction in nociceptive responses to the TMJ formalin test when compared with those at estrus. Then, the selective kappa-opioid receptor antagonist nor-Binaltorphimine (nor-BNI), was co-administered with the formalin. Next, additional groups received the kappa(200 mug) receptor antagonist or 0.9% NaCl 24 hours prior to the periarticular injection of formalin. Co-administration of nor-BNI with formalin into the TMJ region had no significant effect. The pre-injection of selective kappa-opioid receptor antagonist, nor-BNI, significantly enhanced the nociceptive behavioral responses in pregnant females. When applied in the contralateral TMJ, nor-BNI did not affect the magnitude of the nociceptive response induced by formalin. It can be concluded that: 1) The increase of the sex hormone levels, as result of pregnancy, induces a reduction of nociceptive behavioral responses to the TMJ formalin test; 2) the peripheral kappa opioid receptor activation, by endogenous opioid agonists release, is involved in the antinociception to TMJ formalin test, induced by pregnancy. (C) 2004 Elsevier Inc. All rights reserved.76101177118

mu/delta Cooperativity and opposing kappa-opioid effects in nucleus accumbens-mediated antinociception in the rat

We previously demonstrated that noxious peripheral stimulation (e.g. subdermal capsaicin injection in the hind paw) produces antinociception that is mediated by opioid receptors in nucleus accumbens. The current study used the trigeminal jaw-opening nociceptive reflex responses in the rat to assess the role of intra-accumbens mu-, delta- and kappa-opioid receptors in the antinociceptive effect of noxious stimulation and intra-accumbens opioid agonism. Whilst intra-accumbens injection of either the mu-receptor-selective antagonist Cys(2) ,Tyr(3) ,Orn(5) ,Pen(7) amide (CTOP) or the delta-receptor-selective antagonist naltrindole blocked capsaicin-induced antinociception, neither the selective mu-agonist [D-Ala(2) ,N-Me-Phe(4) ,Gly(5) -ol]-enkephalin (DAMGO; 150 or 300 ng) nor the selective delta-agonist D-Pen(2,5) -enkephalin (DPDPE; 150 or 300 ng) alone induced antinociception. Simultaneous injection of DAMGO and DPDPE (150 ng each), however, produced significant antinociception. Capsaicin-induced antinociception was not blocked by the selective kappa-receptor antagonist nor-binaltorphimine, but was blocked by the kappa-agonist U69,593. U69,593 also antagonized the antinociceptive effect of the DAMGO/DPDPE combination. Thus, in nucleus accumbens, mu- and delta- but not kappa-opioid receptors contributed to capsaicin-induced antinociception; selective activation of individual receptor subtypes was insufficient, but coactivation of mu- and delta-opioid receptors induced antinociception, and kappa-receptors appeared to play an antianalgesic role in nucleus accumbens.15586186

Contribution of spinal glutamatergic mechanisms in heterosegmental antinociception induced by noxious stimulation

We evaluated the role of spinal glutamate and substance P receptors in noxious stimulus-induced antinociception (NSIA). NSIA was produced by subdermal capsaicin administration in the hind paw of the rat and measured as attenuation of the jaw-opening reflex. NSIA was completely blocked by spinal intrathecal administration of the selective NMDA receptor antagonist LY235959 as well as the mGluR(5) antagonists MPEP and SIB-1757 and partially attenuated by the selective AMPA/kainate receptor antagonist NBQX; however, neither the mGluR(1) receptor antagonist LY367385 nor the NK1 antagonist L-703,606 affected NSIA. These results suggest that NSIA depends on glutamate. released from the central terminals of the primary afferent nociceptors, acting primarily on NMDA and mGluR(5) receptors. Although substance P is also known to be released by similar stimuli, NK1 receptors do not appear to play a role in NSIA. The implications of these findings in the context of a proposed spinal circuit that mediates NSIA are discussed. (C) 2003 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.1064167117317