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Antinociceptive effects of racemic AM1241 and its chirally synthesized enantiomers: lack of dependence upon opioid receptor activation.
AAPS J 2010; 12(2):147-57AJ

Abstract

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.

Authors+Show Affiliations

Neuroscience and Behavior Program, Department of Psychology, University of Georgia, Athens, Georgia 30602-3013, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20127295

Citation

Rahn, Elizabeth J., et al. "Antinociceptive Effects of Racemic AM1241 and Its Chirally Synthesized Enantiomers: Lack of Dependence Upon Opioid Receptor Activation." The AAPS Journal, vol. 12, no. 2, 2010, pp. 147-57.
Rahn EJ, Zvonok AM, Makriyannis A, et al. Antinociceptive effects of racemic AM1241 and its chirally synthesized enantiomers: lack of dependence upon opioid receptor activation. AAPS J. 2010;12(2):147-57.
Rahn, E. J., Zvonok, A. M., Makriyannis, A., & Hohmann, A. G. (2010). Antinociceptive effects of racemic AM1241 and its chirally synthesized enantiomers: lack of dependence upon opioid receptor activation. The AAPS Journal, 12(2), pp. 147-57. doi:10.1208/s12248-009-9170-8.
Rahn EJ, et al. Antinociceptive Effects of Racemic AM1241 and Its Chirally Synthesized Enantiomers: Lack of Dependence Upon Opioid Receptor Activation. AAPS J. 2010;12(2):147-57. PubMed PMID: 20127295.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antinociceptive effects of racemic AM1241 and its chirally synthesized enantiomers: lack of dependence upon opioid receptor activation. AU - Rahn,Elizabeth J, AU - Zvonok,Alexander M, AU - Makriyannis,Alexandros, AU - Hohmann,Andrea G, Y1 - 2010/02/02/ PY - 2009/08/17/received PY - 2009/12/18/accepted PY - 2010/2/4/entrez PY - 2010/2/4/pubmed PY - 2010/6/16/medline SP - 147 EP - 57 JF - The AAPS journal JO - AAPS J VL - 12 IS - 2 N2 - 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. SN - 1550-7416 UR - https://www.unboundmedicine.com/medline/citation/20127295/Antinociceptive_effects_of_racemic_AM1241_and_its_chirally_synthesized_enantiomers:_lack_of_dependence_upon_opioid_receptor_activation_ L2 - https://dx.doi.org/10.1208/s12248-009-9170-8 DB - PRIME DP - Unbound Medicine ER -