Interaction of histamine and calcitonin gene-related peptide in the formalininduced pain perception in rats

Abstract

Histamine and calcitonin gene-related peptide (CGRP) contribute to the pain perception. The aim of the present study is to clarify the interaction of histamine and CGRP in the perception of inflammatory pain. The effects of a histamine H1 receptor antagonist (pyrilamine, i.p.), an H2 receptor antagonist (ranitidine, i.p.) and a CGRP antagonist (CGRP 8-37, i.t.) on the formalininduced pain was studied in rats. Pyrilamine and ranitidine produced a dose-dependent antinociceptive response in the first and the second phases of the formalin test. A single administration of pyrilamine (1 mg/kg, i.p.), ranitidine (10 mg/kg, i.p.) or CGRP 8-37 (10 μg/μL, i.t.) had no significant effects on the pain perception in the second phase. A combination of CGRP 8-37 and pyrilamine or ranitidine at these sub-effective doses, however, showed nociceptive response in the second phase. Moreover, a histamine (i.t.)-induced hyperalgesia was completely prevented by treatment with GGRP 8-37 at this dose. Our findings have raised the possibility that the CGRP system has interaction with histamine in the perception of inflammatory pain.Pain perception is modulated in the spinal cord by many bioactive substances, such as histamine (38, 39), substance P and calcitonin gene-related peptide (CGRP) (12, 28). Histamine is mostly derived from two cell types, neurons and mast cells. The cell bodies of histaminergic neurons are localized in the tuberomammillary nucleus of the posterior hypothalamus (15). The descending histaminergic neurons terminate at the periaqueductal gray and the dorsal horn of the spinal cord (30,31,43), which is an important site for nociceptive transmission (2). All three histamine H1, H2 and H3 receptors (16) are found in the dorsal horn (26,33,42) and play important roles in the pain perception (22)(23)(24)(25). CGRP is a 37-amino-acid neuropeptide widely distributed in the peripheral and central nervous systems including the dorsal root ganglion (DRG) and its primary afferent terminals in the spinal cord (1, 37). The actions mediated by CGRP type 1 receptor, which is considered to consist of calcitonin receptor-like receptor and receptor activity modifying protein-1 (21), is antagonized by CGRP 8-37 (8). CGRP and its receptors are involved in many stages of pain neurotransmission, especially in the spinal cord (12, 28). As a neurotransmitter, CGRP itself had no obvious effect in pain modulation, but potentiated the excitatory effect induced by substance P or other nociceptive stimuli in the dorsal horn of the spinal cord (3). CGRP stimulated histamine release from mast cells and potentiated histamine ac-

The ability ofH1orH2receptor antagonists or their combination in counteracting the glucocorticoid‐induced alveolar bone loss in rats

“…Group (IV) received intraperitoneal injection of 10 mg/kg/day ranitidine hydrochloride, an H 2 receptor antagonist (H 2 RA). Group (V) received concomitant doses of both H 1 and H 2 receptor antagonists by intraperitoneal injection.…”

The role of histamine in neurogenic inflammation

“…More recently, it has been demonstrated that both the H1 receptor antagonist pyrilamine and the H2 receptor antagonist ranitidine produce dose-dependent antinociceptive responses in the formalin test, and that hyperalgesia induced by intrathecal administration of histamine is attenuated by the GCRP antagonist CGRP 8-37 (Mobarakeh et al, 2011).…”

“…injection of histamine induces CGRP release into the CSF (Bileviciute et al, 1994) and (iii) histamine administered to the nasal mucosa causes CGRP release from the peripheral terminals of trigeminal ganglion in the guinea pig (Tani et al, 1990). Further support for this link between histamine and CGRP is attained from the observed co-localization of the histamine H3 receptor with CGRP on Aδ fibres, with both mediators contributing to a high-threshold mechanical nociceptive effect (Cannon et al, 2007).More recently, it has been demonstrated that both the H1 receptor antagonist pyrilamine and the H2 receptor antagonist ranitidine produce dose-dependent antinociceptive responses in the formalin test, and that hyperalgesia induced by intrathecal administration of histamine is attenuated by the GCRP antagonist CGRP 8-37 (Mobarakeh et al, 2011).Studies with histamine H1 receptor knockout mice have demonstrated that both the receptor and its natural ligand are needed to facilitate pain transmission at both the peripheral and central levels (Mobarakeh et al, 2000;. In addition, using histidine decarboxylase (HDC) gene knockout mice, it was shown that NK 1 receptors in the spinal cord mediate the histamine-induced hyperalgesic responses (Yoshida et al, 2005).…”

Evaluating the Anti-nociceptive and Anti-inflammatory Effects of Ketotifen and Fexofenadine in Rats

“…34 Later on, an interaction between pain-relieving drugs and the brain histaminergic system was reported and multiple analgesic mechanisms suggested for antihistamines such as improgan and even cimetidine. 35 In addition, the role of histamine in different types of pain include central, 36 peripheral, 37 acute 38 chronic 39 or organ related pains such as muscle pain 40 was declared and the number of studies about antihistaminic agents administration as analgesic drugs have been augmented and hyper algesic role of H1 receptors have been proved strongly. 3,20 In this study ketotifen was capable of inhibiting both acute and chronic phase in formalin induced pain model.…”