A considerable amount of evidence suggests that temporomandibular joint (TMJ) pain associated with temporomandibular disorder results, at least in part, from an inflammatory episode. Although histamine can cause pain, it is not clear whether this mediator induces nociception in the TMJ. In this study, we investigated the contribution of endogenous histamine to formal in-induced nociception in the TMJ of rats. We also investigated whether the administration of histamine induces nociception in the TMJ and, if so, whether this effect is mediated by an indirect action on primary afferent nociceptors. Local administration of the H1-receptor antagonist pyrilamine prevented formalin-induced nociception in the TMJ in a dose-dependent manner. Local administration of histamine (250 mu g) in the TMJ induced nociceptive behavior that was inhibited by co-administration of the lidocaine N-ethyl bromide quaternary salt QX-314 (2%) or the selective HI-receptor antagonist pyrilamine (400 mu g). Nociception induced by histamine was also inhibited by pre-treatment with sodium cromoglycate (800 mu g) and by co-administration of the 5-HT3 receptor antagonist tropisetron (400 mu g), while pyrilamine (400 mu g) did not inhibit nociception induced by 5-hydroxytryptamine (5-HT, 250 mu g) in the TMJ. Furthermore histamine, in a dose that did not induce nociception by itself, strongly enhanced 5-HT-induced nociception. Finally, the administration of a sul -threshold dose of 5-HT (100 mu g), but not of histamine (100 mu g), elicited nociception in the TMJ previously challenged with the inflammatory agent carrageenan (100 mu g). In conclusion, these data suggest that histamine induces TMJ nociception by an indirect mechanism involving endogenous release of 5-HT and activation of 5-HT3 receptors on sensory afferents. It is proposed that histamine activates the H1 receptor to induce the release of 5-HT which depolarizes the nociceptor by activating 5-HT3 receptor. (c) 2007 Elsevier Inc. All rights reserved.819765771