Antitussive effect of WIN 55212-2, a cannabinoid receptor agonist

• Published in: European journal of pharmacology Vol. 474; no. 2; pp. 269 - 272
• Main Authors: Morita, Kayo, Kamei, Junzo
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 08.08.2003; Elsevier
• Subjects: Animals; Antitussive Agents - pharmacology; Antitussive Agents - therapeutic use; Antitussive effect; Benzoxazines; Biological and medical sciences; cannabinoid CB 1 receptor; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabinoids - pharmacology; Cannabinoids - therapeutic use; Cough; Cough - drug therapy; Cough - metabolism; Male; Medical sciences; Mice; Mice, Inbred ICR; Morpholines - pharmacology; Morpholines - therapeutic use; Naphthalenes - pharmacology; Naphthalenes - therapeutic use; Pharmacology. Drug treatments; Receptors, Cannabinoid - metabolism; Respiratory system; SR141716A; WIN 55212-2; WIN 55212-2; cannabinoid CB 1 receptor; Antitussive effect; SR141716A; Cough; CB1 cannabinoid receptor; cannabinoid CB1 receptor; Agonist; Cannabinoid receptor; Opioid receptor; Antitussive agent; Antitussive effect Cough
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(03)02009-0

Several lines of evidence indicate that the opioid and cannabinoid systems produce synergistic interactions. The present study examined the opioid receptors involved in the antitussive effect of WIN 55212-2 (( R)-(+)-[2,3-dihydro-5-methyl-3-[4-morpholinylmethyl]-pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl) methanone mesylate), a high-affinity cannabinoid receptor agonist, in mice. WIN 55212-2, at doses of 0.3–3 mg/kg ip, produced a dose-dependent antitussive effect. This antitussive effect of WIN 55212-2 was antagonized by pretreatment with either methysergide (3 mg/kg ip), a 5-HT receptor antagonist, or naloxone (1 mg/kg ip), an opioid receptor antagonist. Furthermore, pretreatment with N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3-carboxamide hydrochloride (SR141716A, 3 mg/kg ip), a cannabinoid CB 1 receptor antagonist, also significantly reduced the antitussive effect of WIN 55212-2. Blockade of μ-opioid receptors by pretreatment with β-funaltrexamine (40 mg/kg sc) significantly reduced the antitussive effect of WIN 55212-2. However, pretreatment with nor-binaltorphimine (20 mg/kg sc), a κ-opioid receptor antagonist, did not affect the antitussive effect of WIN 55212-2. Pretreatment with naloxonazine (35 mg/kg sc), a μ 1-opioid receptor antagonist, also did not affect the antitussive effect of WIN 55212-2. These results indicate that the antitussive effect of WIN 55212-2 is mediated by the activation of cannabinoid CB 1 receptors and μ 2 (naloxonazine-insensitive)-opioid receptors, but not μ 1 (naloxonazine-sensitive)- or κ-opioid receptors.