Antinociceptive Effects of Racemic AM1241 and Its Chirally Synthesized Enantiomers: Lack of Dependence upon Opioid Receptor Activation

• Published in: The AAPS journal 2010-06, Vol.12 (2), p.147-157
• Main Authors: Rahn, Elizabeth J., Zvonok, Alexander M., Makriyannis, Alexandros, Hohmann, Andrea G.
• Format: Article
• Language: English
• Subjects: Analgesics - chemistry; Analgesics - pharmacology; Analgesics, Opioid - pharmacology; Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cannabinoids - chemistry; Cannabinoids - pharmacology; Hot Temperature; Isomerism; Male; Morphine - pharmacology; Naloxone - pharmacology; Narcotic Antagonists - pharmacology; Pain Measurement - drug effects; Pain Threshold - drug effects; Pharmacology/Toxicology; Pharmacy; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - antagonists & inhibitors; Receptors, Opioid - drug effects; Research Article; Structure-Activity Relationship
• ISSN: 1550-7416; 1550-7416
• DOI: 10.1208/s12248-009-9170-8

Cannabinoid CB 2 receptors represent a therapeutic target that circumvents unwanted central side effects ( e . g ., psychoactivity and/or addiction) associated with activation of CB 1 receptors. One of the primary investigative tools used to study functions of the CB 2 receptor is the aminoalkylindole ( R , S )-AM1241. However, ( R , S )-AM1241 has been described as an atypical CB 2 agonist which produces antinociception mediated indirectly by opioid receptors. ( R , S )-AM1241 and its enantiomers, ( R )-AM1241 and ( S )-AM1241, were evaluated for antinociception in response to thermal (Hargreaves) and mechanical (von Frey) stimulation. Pharmacological specificity was established using antagonists for CB 1 (rimonabant [SR141716]) and CB 2 (SR144528). The opioid antagonist naloxone was administered locally in the paw or systemically to evaluate the contribution of opioid receptors to CB 2 -mediated antinociception produced by ( R , S )-AM1241, ( R )-AM1241, and ( S )-AM1241. Comparisons were made with the opioid analgesic morphine. ( R , S )-AM1241, ( R )-AM1241, and ( S )-AM1241 (0.033–10 mg/kg i.p.) produced antinociception to thermal, but not mechanical, stimulation of the hindpaw in naive rats. Antinociception produced by ( R , S )-AM1241 and ( S )-AM1241 exhibited an inverted U-shaped dose response curve. ( R )-AM1241 produced greater antinociception than either ( S )-AM1241 or ( R , S )-AM1241 at the lowest (0.033 and 0.1 mg/kg i.p.) and highest (10 mg/kg i.p.) doses. Similar levels of antinociception were observed at intermediate doses. ( R , S )-AM1241, ( R )-AM1241, and ( S )-AM1241 each produced CB 2 -mediated antinociception that was blocked by SR144528 but not by rimonabant. Local and systemic naloxone blocked morphine-induced antinociception but did not block antinociceptive effects of ( R , S )-AM1241, ( R )-AM1241, or ( S )-AM1241. The antinociceptive effects of the CB 2 -selective cannabinoid ( R , S )-AM1241 and its enantiomers, ( R )-AM1241 and ( S )-AM1241, are not dependent upon opioid receptors.