Antihistamine antinociception is mediated by Gi-protein activation

Abstract

AbstractöThe e¡ect of the i.c.v. administration of antisense oligodeoxynucleotides directed against the K subunit of di¡erent Gi-proteins (anti-GiK 1 , anti-GiK 2 , anti-GiK 3 ) on the antinociception induced by the H 1 -antihistamines was evaluated in the mouse hot-plate test. The administration of diphenhydramine (20 mg kg 31 s.c.), pyrilamine (15 mg kg 31 s.c.) and promethazine (6 mg kg 31 s.c.) produced an increase of the pain threshold which peaked 15 min after injection. Pretreatment with anti-GiK 1 (12.5 Wg per mouse i.c.v.), anti-GiK 2 (25 Wg per mouse i.c.v.) and anti-GiK 3 (25 Wg per mouse i.c.v.), administered 24 and 18 h before test, prevented the antihistamine-induced antinociception. At the highest e¡ective doses, none of the compounds used impaired motor coordination, as revealed by the rota rod test, nor modi¢ed spontaneous motility and inspection activity, as revealed by the hole board test.These results suggest an important role played by the Gi-protein pathway in the transduction mechanism involved in the enhancement of the pain threshold produced by H 1 -antihistamines. ß

The Effect of Histamine H1 Receptor Antagonists on the Morphine-Induced Antinociception in the Acute Trigeminal Model of Nociception in Rats

“…Farzin and Nosrati reported (2007) that IP injection of (20 and 30 mg/kg) dexchlorpheniramine (H 1 receptor antagonist) had an antinociceptive effect in both phases of formalin-induced pain and at a dose of 10 mg/kg antagonized the hyperalgesia induced by intracerebroventricular injection of histamine-trifluoromethyltoluidine (histamine H 1 agonist) [28]. Furthermore, activation of central Gi-protein by peripheral administration of diphenhydramine, pyrilamine, and promethazine suggested as one of the mechanisms that contribute in the analgesic activity of these first-generation antihistamines in the acute model of pain (hot plate test) in mice [29].…”

Ligand-Directed Functional Heterogeneity of Histamine H1Receptors: Novel Dual-Function Ligands Selectively Activate and Block H1-Mediated Phospholipase C and Adenylyl Cyclase Signaling

“…The 5-HT 2C receptor, that is phylogenetically closely related to H 1 receptors (Smit et al, 1999), predominantly couples to G␣ q to activate PLC but also can modulate AC/ cAMP formation through G␣ i (Cussac et al, 2002). Recent evidence also suggests that H 1 receptors may mediate antinociception via G i/o signaling in vivo (Galeotti et al, 2002). GPCRs are not limited to just two different G protein partners; many of the 30 or so different 5-HT receptors couple with several different G proteins and can modulate a halfdozen different intracellular signaling pathways (Raymond et al, 2001).…”

“…Examples of GPCR signaling promiscuity have been demonstrated using native intact cells, primary cultures, and in vivo animal models (Allgeier et al, 1994;Arey et al, 1997;Galeotti et al, 2002), suggesting that multifunctional signaling among GPCRs is not necessarily an artifact of receptor overexpression in clonal cell lines. On the other hand, receptor and/or G protein overexpression might reveal both qualitative and quantitative ligand-GPCR responses that might not be detected in native cell and tissue preparations.…”

Diphenhydramine-induced amnesia is mediated by Gi-protein activation

“…The hole board test was performed according to Galeotti et al (2002). The test consisted of a 40 cm square plane with 16 flush-mounted cylindrical holes (3 cm diameter) distributed four by four in an equidistant, grid-like manner.…”

“…Furthermore, the i.c.v. administration of antisense oligodeoxynucleotides directed against the ␣ subunit of different Gi-proteins (anti-Gi␣ 1 , anti-Gi␣ 2 , anti-Gi␣ 3 ) prevented the antinociception induced by antihistamines (Galeotti et al, 2002). Since Gi-proteins represent the most widespread modulatory signalling pathway in neurones (Holz et al, 1986), we thought it worthwhile to investigate the involvement of Gi proteins into the mechanism of action of the antihistamine diphenhydramine, by means of an antisense strategy.…”