Role of the thalamic submedius nucleus histamine H1 and H 2 and opioid receptors in modulation of formalin-induced orofacial pain in rats.

Histamine and opioid systems are involved in supraspinal modulation of pain. In this study, we investigated the effects of separate and combined microinjections of agonists and antagonists of histamine H1 and H2 and opioid receptors into the thalamic submedius (Sm) nucleus on the formalin-induced orofacial pain. Two guide cannulas were implanted into the right and left sides of the Sm in ketamine- and xylazine-anesthetized rats. Orofacial formalin pain was induced by subcutaneous injection of a diluted formalin solution (50 μl, 1.5%) into the vibrissa pad. Face rubbing durations were recorded at 3-min blocks for 45 min. Formalin produced a biphasic pain response (first phase: 0-3 min and second phase: 15-33 min). Separate and combined microinjections of histamine H1 and H2 receptor agonists, 2-pyridylethylamine (2-PEA) and dimaprit, respectively, and opioid receptor agonist, morphine, attenuated the second phase of pain. The analgesic effects induced by 2-PEA, dimaprit, and morphine were blocked by prior microinjections of fexofenadine (a histamine H1 receptor antagonist), famotidine (a histamine H2 receptor antagonist), and naloxone (an opioid receptor antagonist), respectively. Naloxone also prevented 2-PEA- and dimaprit-induced antinociception, and the analgesic effect induced by morphine was inhibited by fexofenadine and famotidine. These results showed the involvement of histamine H1 and H2 and opioid receptors in the Sm modulation of orofacial pain. Opioid receptor might be involved in analgesia induced by activation of histamine H1 and H2 receptors and vice versa.