Abstract
Side effects of marijuana-based drugs and synthetic analogs of Δ9-tetrahydrocannabinol (Δ9-THC), including sedation and dysphoria, have limited their therapeutic application. Ajulemic acid (AJA), a side-chain synthetic analog of Δ8-THC-11-oic acid, has been reported to have anti-inflammatory properties without producing undesired psychoactive effects. Moreover, it has been suggested that AJA does not interact with cannabinoid receptors to produce its pharmacological effects. The aim of the present study was to conduct a thorough evaluation of the pharmacological effects of AJA then to determine whether actions at cannabinoid receptor (CB)1 mediated these effects. This study evaluated the psychoactive and analgesic effects of AJA by examining its cannabimimetic properties in ICR mice (i.e., antinociception, catalepsy, hypothermia, and hypomobility), its discriminative stimulus effects in Long Evans rats trained in a two-lever Δ9-THC (3.0 mg/kg) versus vehicle drug discrimination procedure, and its antihyperalgesia effects in a rat model of inflammatory pain [complete Freund's adjuvant (CFA)-induced mechanical hyperalgesia]. Lastly, antagonism tests with SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride], CB1 receptor antagonist, were conducted. These studies demonstrated that AJA shares a number of CB1-mediated pharmacological properties with Δ9-THC, including cannabimimetic, discriminative stimulus, and antihyperalgesic effects. Furthermore, a separation between doses that produced antinociception and those that produced the other pharmacological effects in mice was not observed. Moreover, AJA showed nearly equipotency for therapeutic efficacy in the CFA model and for substitution in Δ9-THC discrimination. In summary, this study shows that AJA, like Δ9-THC, exhibits psychoactive and therapeutic effects at nearly equal doses in preclinical models, suggesting similar limitations in their putative therapeutic profiles.
Footnotes
-
This work was supported by National Institute on Drug Abuse Grants DA-05488 and DA-03672 and by Virginia Commonwealth University Institute of Drug and Alcohol Studies.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.106.111625.
-
ABBREVIATIONS: Δ9-THC, Δ9-tetrahydrocannabinol; AJA, ajulemic acid (1′,1′-dimethylheptyl-Δ8-tetrahydrocannabinol-11-oic acid); CFA, complete Freund's adjuvant; MPE, percentage of maximal possible effect in tail-flick test; SR 141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride; SR144528, N-[-(1S)-endo-1,3,3-trimethyl bicyclo [2,2,1] heptan-2-yl]-5-(4-chloro-3-methyl-phenyl)-1-(4methylbenzyl)-pyrazole-3-carboxamide; FR-10, fixed-ratio 10; VEH, vehicle; CB, cannabinoid receptor; ANOVA, analysis of variance; CL, confidence limit.
- Received July 26, 2006.
- Accepted November 10, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|