Interaction between histamine and morphine at the level of the hippocampus in the formalin- induced orofacial pain in rats Esmaeal Tamaddonfard 1 , Amir Erfanparast 1 , Amir Abbas Farshid 2 , Emad Khalilzadeh 1 Division of Physiology, Department of Basic Sciences, Division of Pathology, Department of Pathobiology, Faculty of Veterinary Medicine, Urmia University, Urmia 57153-1177, Iran Correspondence: Esmaeal Tamaddonfard, e-mail: e_tamaddonfard@yahoo.com and e_tamaddonfard@urmia.ac.ir Abstract: The present study explored the interaction between histaminergic and opioidergic systems at the level of the hippocampus in modu- lation of orofacial pain by intra-hippocampal microinjections of histamine, pyrilamine (an antagonist of histamine H 1 receptors), ranitidine (an antagonist of histamine H 2 receptors), morphine (an opioid receptor agonist) and naloxone (an opioid receptor antago- nist) in separate and combined treatments. Orofacial pain was induced by subcutaneous (sc) injection of formalin (50 μl, 1%) in the upper lip region and the time spent face rubbing was recorded in 3 min blocks for 45 min. Formalin (sc) produced a marked biphasic (first phase: 0–3 min, second phase: 15–33 min) pain response. Histamine and morphine suppressed both phases of pain. Histamine increased morphine-induced antinociception. Pyrilamine and ranitidine had no effects when used alone, whereas pretreatments with pyrilamine and ranitidine prevented histamine- and morphine-induced antinociceptive effects. Naloxone alone non-significantly in- creased pain intensity and inhibited the antinociceptive effects of morphine and histamine. The results of the present study indicate that at the level of the hippocampus, histamine through its H 1 and H 2 receptors, mediates orofacial region pain. Moreover, morphine via a naloxone-reversible mechanism produces analgesia. In addition, both histamine H 1 and H 2 receptors, as well as opioid recep- tors may be involved in the interaction between histamine and morphine in producing analgesia. Key words: histamine, histamine H and H receptors, morphine, naloxone, hippocampus, orofacial formalin test, rats Abbreviations: icv – intracerebroventricular, PAG – periaque- ductal gray, SNO – subnucleus oralis Introduction The hippocampus is involved in a variety of biologi- cal functions including learning and memory, stress, immunity, energy intake, body weight regulation and pain modulation [11, 21–24, 48]. Histaminergic end- ings and its H 1 ,H 2 and H 3 receptors are distributed in various parts of limbic system [37], and mediate some of functions of the hippocampus such as anxiety, arousal state, hibernation, neurotransmission, learning and memory [2, 36, 49]. On the other hand, opioid re- ceptors are expressed in the hippocampal formation and are involved in mediation of hippocampal func- tions including adult neurogenesis, the action of gona- dal hormones, development of neonatal transmitter system and pain [12, 13, 18]. 423