Effects of administration of histamine and its H1, H2, and H3 receptor antagonists into the primary somatosensory cortex on inflammatory pain in rats

Document Type : Original Article


1 Department of Basic Sciences, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran

2 Faculty of Veterinary Medicine, Urmia University, Urmia, Iran



Objective(s): The present study investigated the effects of microinjection of histamine and histamine H1, H2, and H3
receptor antagonists, chlorpheniramine, ranitidine and thioperamide, respectively into the primary somatosensory cortex (PSC) on inflammatory pain.
Material and Methods:
Two stainless steel guide canulas were bilaterally implanted into the PSC of anaesthetized rats. Inflammatory pain was induced by subcutaneous (SC) injection of formalin (50 μl, 2.5%) in the ventral surface of right hind paw. Time durations of licking/biting of the injected paw were recorded as a pain measure.
Formalin produced a biphasic pattern of licking/biting of the injected paw. Histamine at doses of 0.5, 1, and 2 μg decreased the intensity of pain. Chlorpheniramine and ranitidine at the same doses of 1 and 4 μg had no effects, whereas thioperamide at a dose of 4 μg suppressed both phases of formalin-induced pain. Pretreatments with chlorpheniramine and ranitidine at the same dose of 4 μg prevented histamine (2 μg)-induced antinociception. Antinociceptive effects were observed when thioperamide at doses of 1 and 4 μg was used with 0.25 and 1 μg of histamine, respectively. The antinociceptive effects induced by histamine (2 μg) and thioperamide (4 μg) were prevented by prior treatment with naloxone (4 μg).
These results indicate that at PSC levels, histamine through post-synaptic H1, H2, and pre-synaptic H3 receptors might be involved in pain modulation. The endogenous opioid system may be involved in histamine- and thioperamide-induced antinociception.


Almeida TF, Roizenblatt S, Tufik S. Afferent pain pathways: a neuroanatomical study. Brain Res 2004; 1000:40-56.
Melzack R. From the gate to the neuromatrix. Pain 1999; 6:S121-S126.
Ossipov MH, Dussor GD, Porreca F. Central modulation of pain. J Clin Invest 2010; 120: 3779-3787.
Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell 2009; 16:267-284.
Ploner M, Schuitzler A. Cortical representation of pain. Nervenarzt 2004; 75: 962-969.
Xie YF, Huo FQ, Tang JS. Cerebral cortex modulation of pain. Acta Pharmacol Sin 2009; 30: 31-41.
Kenshalo DR, Iwata K, Sholas M, Thomas DA. Response properties and organization of nociceptive neurons in area 1 of monkey primary somatosensory cortex. J Neurophysiol 2000; 84:719-729.
Kuo CC, Yen CT. Comparison of anterior cingulated and primary somatosensory neuronal responses to noxious laser-heat stimuli in conscious, behaving rats. J Neurophysiol 2005; 94:1825-1836.
Shih YYI, Chiang YC, Chen JC, Huang CH, Chen YY, Liu RS, et al. Brain nociceptive imaging in rats using 18F- fluorodeoxyglucose small animal positron emission tomography. Neuroscience 2008; 155:1221-1226.
Tamaddonfard E, Rahimi S. Central effect of histamine and peripheral effect of histidine on the formalin-induced pain response in mice. Clin Exp Pharmacol Physiol 2004; 31:518-522.
Mojtahedin A, Tamaddonfard E, Zanbouri A. Antinociception induced by central administration of histamine in the formalin test in rats. Indian J Physiol Pharmacol 2008; 52:249-254.
Thoburn KK, Hough LB, Nalwalk JW, Mischler SA. Histamine-induced modulation of nociceptive responses. Pain 1994; 58:29-37.
Huang L, Adachi N, Nagaro T, Liu K, Arai T. Histaminergic involvement in neuropathic pain produced by partial ligation of the sciatic nerve in rats. Reg Anesth Pain Med 2007; 32:124-129.
Khalilzadeh E, Tamaddonfard E, Farshid AA, Erfanparast A. Microinjection of histamine into the dentate gyrus produces antinociception in the formalin test. Pharmacol Biochem Behav 2010; 97:325-332.
Khalilzadeh E, Tamaddonfard E, Farshid AA, Erfanparast A. Thioperamide-induced antinociception is mediated through endogenous opioid system in the dentate gyrus of adult rats. Vet Res Forum 2010; 1: 166-173.
Paxinos G, Watson C. The rat brain in stereotaxic coordinates. Compact 3rd ed., San Diego, USA: Academic Press; 1997.
Erfanparast A, Tamaddonfard E, Farshid AA, Khalilzadeh E. Effect of microinjection of histamine into the dorsal hippocampus on the orofacial formalin-induced pain in rats. Eur J Pharmacol 2010; 627:119-123.
Erfanparast A, Tamaddonfard E, Farshid AA, Khalilzadeh E. Antinociceptive effect of morphine microinjections into the dorsal hippocampus in the formalin-induced orofacial pain in rats. Vet Res Forum 2010; 1:83-89.
Tamaddonfard E, Erfanparast A, Farshid AA, Khalilzadeh E. Interaction between histamine and morphine at the level of the hippocampus in the formalin-induced orofacial pain in rats. Pharmacol Rep 2011; 63:423-432.
Abbott FV, Bonder M. Options for management of acute pain in the rat. Vet Res 1997; 140:553-557.
Tjolsen A, Berge OG, Hunskaar S, Rosland GH, Hole K. The formalin test: an evaluation of the method. Pain 1992; 51:5-17.
Porro CA, Cavazzuti M. Spatial and temporal aspects of spinal cord and brainstem activation in the formalin pain model. Prog Neurobiol 1993; 41:565-607.
Capone F, Aloisi AM. Refinement of pain evaluation techniques. Ann Ist Super Sanita 2004; 40:223-229.
Raboisson P, Dallel R. The orofacial formalin test. Neurosci Biobehav Rev 2004; 28:219-226.
Hong Y, Abbott FV. Behavioral effects of intraplantar injection of inflammatory mediators in the rat. Neuroscience 1994; 63:827-836.
Parada CA, Tambeli CH, Cunha FQ, Ferreira SH. The major role of histamine and 5-hydroxytryptamine in formalin-iduced nociception. Neuroscience 2001; 102:937-944.
Tamaddonfard and Hamzeh-Gooshchi Histamine in primary somatosensory cortex and formalin pain
Iran J Basic Med Sci, Vol. 17, No. 1, Jan 2014 61
Sakurada S, Orito T, Furuta S, Watanabe H, Mobarake JI, Yanai K, et al. Intrathecal histamine induces spinally mediated behavioral responses through tachykinin NK1 receptors. Pharmacol Biochem Behav 2003; 74:487-493.
Thoburn KK, Hough LB, Nalwalk JW, Mischler SA. Histamine-induced modulation of nociceptive responses. Pain 1994; 58:29-37.
Bushnell MC, Duncan CH, Hofbauer RK, Ha B,Chen JI, Carrier B. Pain perception: is there a role for primary sensory cortex? Proc Nalt Acad Sci USA 1999; 96:7705-7708.
Schwartz JC, Arrang JM, Garbarg M, Pollard H, Rouat M. Histaminergic transmission in the mammalian brain. Physiol Rev 1991; 71:1-51.
Pillot C, Heron A, Cochois V, Tardivel-Lacombe J, Ligneau X, Schwartz JC, et al. A detailed mapping of the histamine H3 receptor and its gene transcripts in rat brain. Neuroscience 2002; 114:173-193.
Jin CY, Panula P. The laminar histamine receptor system in human prefrontal cortex suggests multiple levels of histaminergic regulation. Neuroscience 2005; 132:137-149.
Van Ruitenbeek P, Vermeeren A, Smulders FTY, Sambeth A, Reidel WJ. Histamine H1 receptor blockade predominantly impairs sensory processes in human sensorimotor performance. Br J Pharmacol 2009; 157:76-85.
Kawarada K, Kamata K, Matsumoto N. Effects of conditioning stimulation of the central amygdaloid nucleus on tooth pulp-driven neurons in the cat somatosensory cortex (SI). Jpn J Physiol 1999; 49:485-497.
Arrang JM, Garbarg M, Lancelot JC, Lecomte JM, Pollard H, Robba M, et al. Highly potent and selective ligands for histamine H3-receptors. Nature 1987; 327:117-123.
Pollard H, Moreau J, Arrange JM, Schwartz JC. A detailed authoradiographic mapping of histamine H3 receptors in rat brain areas. Neuroscience 1993; 52:169-189.
Brown RE, Stevens DR, Haas HL. The physiology of brain histamine. Prog Neurobiol 2001; 63:637-672.
Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev 2008; 88:1183-1241.
Munari L, Provensi G, Passani MB, Blandina, P. Selective brain region activated by histamine H3 receptor antagonist/inverse agonist ABT-239 enhances acetylcholine and histamine release and increased c-Fos expression. Neuropharmacology 2013; 70:131-140.
Karlstedt K, Ahman MJ, Anichtchik OV, Soinila S, Panula P. Expression of the H3 receptor in the developing CNS and brown fat suggests novel roles for histamine. Mol Cell Neurosci 2003; 24: 614-623.
Cannon KE, Chazot PL, Hann V, Shenton F, Hough LB, Rice FL. Immunohistichemical localization of histamine H3 receptors in rodent skin, dorsal root ganglion, superior cervical ganglion and spinal cord: potential antinociceptive targets. Pain 2007a; 129:76–92.
Hough LB, Rice FL. H3 receptors and pain modulation: peripheral, spinal and brain interactions. J Pharmacol Exp Ther 2011; 336: 30-37.
Fernandez-Duenas V, Ciruela F, Gandia J, Sanchez S, Planas E, Poveda R. Histamine H3 receptor activation potentiates peripheral opioid-mediated antinociception: substance P role in peripheral inflammation in mice. Eur J Pharmacol 2010; 638:72-77.
Cannon KE, Leurs R, Hough LB. Activation of peripheral and spinal histamine H3 receptors inhibits formalin-induced inflammation and nociception, respectively. Pharmacol Biochem Behav 2007b; 88:122-129.
Malmberg-Aiello P, Lamberti C, Ghelardini C, Giotti A, Bartolini A. Role of histamine in rodent antinociception. Br J Pharmacol 1994; 111:1269-1279.
Trescot AM, Datta S, Lee M, Hansen H. Opioid Pharmacology. Pain Physician 2008; 11:133-153.
Xie YF, Wang J, Huo FQ, Jia H, Tang JS. Mu but not delta and kappa opioid receptor involvement in ventrolateral orbital cortex opioid-evoked antinociception in formalin test rats. Neuroscience 2004; 126:717-726.
Zhao M, Wang JY, Jia H, Tang JS. Mu- but not delta- and kappa-opioid receptors in the ventrolateral orbital cortex mediate opioid-induced antiallodynia in a rat neuropathic pain model. Brain Res 2006; 1076:68-77.
Mobarakeh JI, Takahashi K, Yanai K. Enhanced morphine-induced antinociception in histamine H3 receptor gene knockout mice. Neuropharmacology 2009; 57:409-914.
Pollard M. Ionotropic glutamate receptor-mediated responses in the rat primary somatosensory cortex evoked by noxious and innocuous cutaneous stimulation in vivo. Exp Brain Res 2000; 131:282-292.
Wang N, Wang JY, Luo F. Corticofugal output facilitate acute, but inhibit chronic pain in rats. Pain 2009; 142:108-115.