Blockade of beta(1)-, beta(2)- and beta(3)-adrenoceptors in the temporomandibular joint induces antinociception especially in female rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Background Temporomandibular joint (TMJ) receives rich sympathetic innervations that may contribute to TMJ pain through the local release of sympathomimetic amines. The aim of this study was to determine whether blockade of beta-adrenoceptors in the TMJ of male and female rats reduces formalin-induced TMJ nociceptive behaviour. Methods We co-administrated each one of the selective beta 1-, beta 2- and beta 3-adrenoceptors antagonists, atenolol, ICI 118.551 and SR59230A, respectively, with formalin in the TMJ of male and proestrus and dioestrus female rats. Because intra-temporomandibular joint formalin induces significantly different concentration-dependent responses among the three groups, with dioestrus females showing greater responses than males or proestrus females, equi-nociceptive formalin concentrations were used to test the effects of the beta-adrenoceptor antagonists. Results We found that atenolol, ICI 118.551 and SR59230A significantly reduced formalin-induced TMJ nociception in a dose response fashion in both males and females. However, a lower dose of each beta-adrenoceptor antagonist was sufficient to significantly reduce nociceptive responses in females than in males. Administration of the highest doses of each beta-adrenoceptor antagonist in the TMJ contralateral to that receiving formalin did not affect formalin-induced nociception in males and females, confirming the local action of the beta-adrenoceptor antagonists. Conclusions We conclude that blockade of beta-adrenoceptors in the temporomandibular joint suppresses formalin-induced TMJ nociceptive behaviour in both males and females but females are more responsive. These findings suggest that the use of beta-blockers in the treatment of TMJ pain might be of benefit, especially in females.16913021310Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Blockade of β1‐, β2‐ and β3‐adrenoceptors in the temporomandibular joint induces antinociception especially in female rats

Background Temporomandibular joint (TMJ) receives rich sympathetic innervations that may contribute to TMJ pain through the local release of sympathomimetic amines. The aim of this study was to determine whether blockade of β‐adrenoceptors in the TMJ of male and female rats reduces formalin‐induced TMJ nociceptive behaviour. Methods We co‐administrated each one of the selective β1‐, β2‐ and β3‐adrenoceptors antagonists, atenolol, ICI 118.551 and SR59230A, respectively, with formalin in the TMJ of male and proestrus and dioestrus female rats. Because intra‐temporomandibular joint formalin induces significantly different concentration‐dependent responses among the three groups, with dioestrus females showing greater responses than males or proestrus females, equi‐nociceptive formalin concentrations were used to test the effects of the β‐adrenoceptor antagonists. Results We found that atenolol, ICI 118.551 and SR59230A significantly reduced formalin‐induced TMJ nociception in a dose response fashion in both males and females. However, a lower dose of each β‐adrenoceptor antagonist was sufficient to significantly reduce nociceptive responses in females than in males. Administration of the highest doses of each β‐adrenoceptor antagonist in the TMJ contralateral to that receiving formalin did not affect formalin‐induced nociception in males and females, confirming the local action of the β‐adrenoceptor antagonists. Conclusions We conclude that blockade of β‐adrenoceptors in the temporomandibular joint suppresses formalin‐induced TMJ nociceptive behaviour in both males and females but females are more responsive. These findings suggest that the use of β‐blockers in the treatment of TMJ pain might be of benefit, especially in females16913021310CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPsem informaçã

Gonadal Hormones Modulate The Responsiveness To Local β-blocker-induced Antinociception In The Temporomandibular Joint Of Male And Female Rats.

We have previously demonstrated that blockade of β-adrenoreceptors (β-AR) located in the temporomandibular joint (TMJ) of rats suppresses formalin-induced TMJ nociceptive behaviour in both male and female rats, but female rats are more responsive. In this study, we investigated whether gonadal hormones modulate the responsiveness to local β-blocker-induced antinociception in the TMJ of rats. Co-administration of each of the selective β1 (atenolol), β2 (ICI 118.551) and β3 (SR59230A)-AR antagonists with equi-nociceptive concentrations of formalin in the TMJ of intact, gonadectomized and hormone-treated gonadectomized male and female rats. Atenolol, ICI 118.551 and SR59230A significantly reduced formalin-induced TMJ nociception in a dose response fashion in all groups tested. However, a lower dose of each β-AR antagonist was sufficient to significantly reduce nociceptive responses in gonadectomized but not in intact and testosterone-treated gonadectomized male rats. In the female groups, a lower dose of β1 -AR antagonist was sufficient to significantly reduce nociceptive responses in gonadectomized but not in intact or gonadectomized rats treated with progesterone or a high dose of oestradiol; a lower dose of β2 -AR antagonist was sufficient to significantly reduce nociceptive responses in gonadectomized but not in intact and gonadectomized rats treated with low or high dose of oestradiol. Gonadal hormones may reduce the responsiveness to local β-blocker-induced antinociception in the TMJ of male and female rats. However, their effect depends upon their plasma level, the subtype of β-AR and the dose of β-blockers used

Gonadal hormones modulate the responsiveness to local β‐blocker‐induced antinociception in the temporomandibular joint of male and female rats

We have previously demonstrated that blockade of β‐adrenoreceptors (β‐AR) located in the temporomandibular joint (TMJ) of rats suppresses formalin‐induced TMJ nociceptive behaviour in both male and female rats, but female rats are more responsive. In this study, we investigated whether gonadal hormones modulate the responsiveness to local β‐blocker‐induced antinociception in the TMJ of rats. Methods Co‐administration of each of the selective β1 (atenolol), β2 (ICI 118.551) and β3 (SR59230A)‐AR antagonists with equi‐nociceptive concentrations of formalin in the TMJ of intact, gonadectomized and hormone‐treated gonadectomized male and female rats. Results Atenolol, ICI 118.551 and SR59230A significantly reduced formalin‐induced TMJ nociception in a dose response fashion in all groups tested. However, a lower dose of each β‐AR antagonist was sufficient to significantly reduce nociceptive responses in gonadectomized but not in intact and testosterone‐treated gonadectomized male rats. In the female groups, a lower dose of β1‐AR antagonist was sufficient to significantly reduce nociceptive responses in gonadectomized but not in intact or gonadectomized rats treated with progesterone or a high dose of oestradiol; a lower dose of β2‐AR antagonist was sufficient to significantly reduce nociceptive responses in gonadectomized but not in intact and gonadectomized rats treated with low or high dose of oestradiol. Conclusion Gonadal hormones may reduce the responsiveness to local β‐blocker‐induced antinociception in the TMJ of male and female rats. However, their effect depends upon their plasma level, the subtype of β‐AR and the dose of β‐blockers used196772780FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2009/16991-0; 2010/19872-

Alterações histológicas de glândulas submandibulares e testículos induzidas por dietas à base de soja e dieta zinco deficiente em ratos.

The purpose of this study was to examine in rats the histologic alterations of the submandibular glands and testicles induced by soy diets and zinc deficient diet. The zinc deficiency produced testicles alterations including seminiferous tubulus atrophy, germinative epithelium degeneration, spermatogenesis alterations and a significant atrophy of the submandibular glands which presented no much delimitated acines. The soy diet without complementations also compromised the spermatogenesis by showing seminiferous tubulus atrophied and a reduction of the germinative epithelium. The soy diet complemented by saline and vitaminic mixtures didn't produced testicles alterations but its induced in the submandibular glands a hypertrophy of the ductal component mainly in relation to the granular component

Development of a behavioral model of TMJ pain in rats: the TMJ formalin test

CAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL E NÍVEL SUPERIORFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOTemporomandibular joint (TMJ) pain conditions are poorly understood. Since formalin is a noxious stimulus widely used in animal behavioral experiments for studying pain mechanisms, the aim of this study was to develop a behavioral model to study the TMJ pain conditions by characterizing the nociceptive behavioral responses induced by the injection of formalin into the TMJ region of rats. NaCl (0.9%) or different concentrations of formalin (0.5, 1.5, 2.5 or 5%) were administrated into the TMJ region. The formalin-induced behavioral responses characterized by moving the mandible, rubbing the orofacial region and flinching the head quickly were quantified for 45 min. The TMJ injection of formalin significantly increased the asymmetrical orofacial rubbing and head flinching behaviors, but not the movement of the mandible with concentrations of 1.5% and above (P<0.05, Dunn's test) when compared with the NaCl (0.9%) injection. These responses were significantly reduced (P<0.05, Mann-Whitney test) by the co-application of lidocaine N-ethyl bromide quaternary salt, QX-314 (2%), and by the administration of intraperitoneal morphine (4 mg/kg) 30 min prior to the TMJ formalin injection. This study demonstrates that the injection of formalin into the TMJ region of rats produces quantitative nociceptive behaviors constituting a novel behavioral model for TMJ pain.Temporomandibular joint (TMJ) pain conditions are poorly understood. Since formalin is a noxious stimulus widely used in animal behavioral experiments for studying pain mechanisms, the aim of this study was to develop a behavioral model to study the TMJ pain conditions by characterizing the nociceptive behavioral responses induced by the injection of formalin into the TMJ region of rats. NaCl (0.9%) or different concentrations of formalin (0.5, 1.5, 2.5 or 5%) were administrated into the TMJ region. The formalin-induced behavioral responses characterized by moving the mandible, rubbing the orofacial region and flinching the head quickly were quantified for 45 min. The TMJ injection of formalin significantly increased the asymmetrical orofacial rubbing and head flinching behaviors, but not the movement of the mandible with concentrations of 1.5% and above (P<0.05, Dunn's test) when compared with the NaCl (0.9%) injection. These responses were significantly reduced (P<0.05, Mann–Whitney test) by the co-application of lidocaine N-ethyl bromide quaternary salt, QX-314 (2%), and by the administration of intraperitoneal morphine (4 mg/kg) 30 min prior to the TMJ formalin injection. This study demonstrates that the injection of formalin into the TMJ region of rats produces quantitative nociceptive behaviors constituting a novel behavioral model for TMJ pain942185191CAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL E NÍVEL SUPERIORFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL E NÍVEL SUPERIORFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOsem informaçãosem informaçã

Peripheral P2x7 Receptor-induced Mechanical Hyperalgesia Is Mediated By Bradykinin.

P2X7 receptors play an important role in inflammatory hyperalgesia, but the mechanisms involved in their hyperalgesic role are not completely understood. In this study, we hypothesized that P2X7 receptor activation induces mechanical hyperalgesia via the inflammatory mediators bradykinin, sympathomimetic amines, prostaglandin E2 (PGE2), and pro-inflammatory cytokines and via neutrophil migration in rats. We found that 2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate triethylammonium salt (BzATP), the most potent P2X7 receptor agonist available, induced a dose-dependent mechanical hyperalgesia that was blocked by the P2X7 receptor-selective antagonist A-438079 but unaffected by the P2X1,3,2/3 receptor antagonist TNP-ATP. These findings confirm that, although BzATP also acts at both P2X1 and P2X3 receptors, BzATP-induced hyperalgesia was mediated only by P2X7 receptor activation. Co-administration of selective antagonists of bradykinin B1 (Des-Arg(8)-Leu(9)-BK (DALBK)) or B2 receptors (bradyzide), β1 (atenolol) or β2 adrenoceptors (ICI 118,551), or local pre-treatment with the cyclooxygenase inhibitor indomethacin or the nonspecific selectin inhibitor fucoidan each significantly reduced BzATP-induced mechanical hyperalgesia in the rat hind paw. BzATP also induced the release of the pro-inflammatory cytokines tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6 and cytokine-induced neutrophil chemoattractant-1 (CINC-1), an effect that was significantly reduced by A-438079. Co-administration of DALBK or bradyzide with BzATP significantly reduced BzATP-induced IL-1β and CINC-1 release. These results indicate that peripheral P2X7 receptor activation induces mechanical hyperalgesia via inflammatory mediators, especially bradykinin, which may contribute to pro-inflammatory cytokine release. These pro-inflammatory cytokines in turn may mediate the contributions of PGE2, sympathomimetic amines and neutrophil migration to the mechanical hyperalgesia induced by local P2X7 receptor activation.277163-7

Sexual dimorphism in the antinociception mediated by kappa opioid receptors in the rat temporomandibular joint

This study assessed the effect of the kappa opioid receptor agonist U50,488 administered into the rat temporomandibular joint (TMJ) on nociceptive behavioral responses evoked by formalin injected into the same site. Groups consisted of females, stratified into proestrus and diestrus phases of the estrous cycle, and males. Intra-TMJ formalin induced significantly different dose-dependent responses among the three groups, with diestrus females showing greater responses than males or proestrus females; therefore, equi-nociceptive formalin doses were chosen to test the effects of U50,488. U50,488 significantly reduced formalin-induced nociceptive behavior in all groups, but the reduction was significantly greater in females, especially those in diestrus. Pre-injection of the selective kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI) into the same site significantly attenuated the effect of U50488; U50,488 injection into the contralateral TMJ failed to reduce nociceptive behavior. These findings support a role for kappa opioid receptors local to the site of inflammation to modulate inflammatory pain. Furthermore, since plasma levels of ovarian hormones are low during diestrus, these findings are consistent with the suggestion that sex hormones may play an antagonistic role in these peripheral kappa-mediated effects372325025

Development of a behavioral model of TMJ pain in rats: the TMJ formalin test

Abstract Temporomandibular joint (TMJ) pain conditions are poorly understood. Since formalin is a noxious stimulus widely used in animal behavioral experiments for studying pain mechanisms, the aim of this study was to develop a behavioral model to study the TMJ pain conditions by characterizing the nociceptive behavioral responses induced by the injection of formalin into the TMJ region of rats. NaCl (0.9%) or different concentrations of formalin (0.5, 1.5, 2.5 or 5%) were administrated into the TMJ region. The formalin-induced behavioral responses characterized by moving the mandible, rubbing the orofacial region and flinching the head quickly were quantified for 45 min. The TMJ injection of formalin significantly increased the asymmetrical orofacial rubbing and head flinching behaviors, but not the movement of the mandible with concentrations of 1.5% and above (P , 0:05, Dunn&apos;s test) when compared with the NaCl (0.9%) injection. These responses were significantly reduced (P , 0:05, Mann-Whitney test) by the co-application of lidocaine N-ethyl bromide quaternary salt, QX-314 (2%), and by the administration of intraperitoneal morphine (4 mg/kg) 30 min prior to the TMJ formalin injection. This study demonstrates that the injection of formalin into the TMJ region of rats produces quantitative nociceptive behaviors constituting a novel behavioral model for TMJ pain

Effect Of Pain Chronification And Chronic Pain On An Endogenous Pain Modulation Circuit In Rats.

We tested the hypothesis that chronic pain development (pain chronification) and ongoing chronic pain (chronic pain) reduce the activity and induce plastic changes in an endogenous analgesia circuit, the ascending nociceptive control. An important mechanism mediating this form of endogenous analgesia, referred to as capsaicin-induced analgesia, is its dependence on nucleus accumbens μ-opioid receptor mechanisms. Therefore, we also investigated whether pain chronification and chronic pain alter the requirement for nucleus accumbens μ-opioid receptor mechanisms in capsaicin-induced analgesia. We used an animal model of pain chronification in which daily subcutaneous prostaglandin E2 (PGE2) injections into the rat's hind paw for 14 days, referred to as the induction period of persistent hyperalgesia, induce a long-lasting state of nociceptor sensitization referred to as the maintenance period of persistent hyperalgesia, that lasts for at least 30 days following the cessation of the PGE2 treatment. The nociceptor hypersensitivity was measured by the shortening of the time interval for the animal to respond to a mechanical stimulation of the hind paw. We found a significant reduction in the duration of capsaicin-induced analgesia during the induction and maintenance period of persistent mechanical hyperalgesia. Intra-accumbens injection of the μ-opioid receptor selective antagonist Cys(2),Tyr(3),Orn(5),Pen(7)amide (CTOP) 10 min before the subcutaneous injection of capsaicin into the rat's fore paw blocked capsaicin-induced analgesia. Taken together, these findings indicate that pain chronification and chronic pain reduce the duration of capsaicin-induced analgesia, without affecting its dependence on nucleus accumbens μ-opioid receptor mechanisms. The attenuation of endogenous analgesia during pain chronification and chronic pain suggests that endogenous pain circuits play an important role in the development and maintenance of chronic pain.28637-4