[Epub ahead of print]
DIFFERENTIAL DRUG-DRUG INTERACTIONS OF THE SYNTHETIC CANNABINOIDS JWH-018 AND JWH-073: IMPLICATIONS FOR DRUG ABUSE LIABILITY AND PAIN THERAPY.
Brents LK, Zimmerman SM, Saffell AR, Prather PL, Fantegrossi WE.
Source
University of Arkansas for Medical Sciences.
Abstract
Marijuana substitutes often contain blends of multiple psychoactive synthetic cannabinoids (SCBs), including the prevalent SCBs JWH-018 and JWH-073. Because SCBs are frequently used in combinations, we hypothesized that co-administering multiple SCBs induces synergistic drug-drug interactions. Drug-drug interactions between JWH-018 and JWH-073 were investigated in vivo for Δ9-tetrahydrocannabinol (Δ9-THC)-like discriminative stimulus effects, analgesia, task disruption, and hypothermia by administering combinations (JWH-018: JWH-073) of these drugs to mice in assays of Δ9-THC discrimination, tail-immersion, and food-maintained responding, and measuring rectal temperature, respectively. Synergism occurred in the Δ9-THC discrimination assay for two constant dose ratio combinations (1:3 and 1:1). A 1:1 and 2:3 dose ratio induced additivity and synergy, respectively, in the tail-immersion assay. Both 1:1 and 2:3 dose ratios were additive for hypothermia, while a 1:3 dose ratio induced sub-additive suppression of food-maintained responding. In vitro drug-drug interactions were assessed using competition receptor binding assays employing mouse brain homogenates and CB1R-mediated inhibition of adenylyl cyclase activity in Neuro2A wild-type (Neuro2AWT) cells. Interestingly, synergy occurred in the competition receptor binding assay for two dose ratios (1:5 and 1:10), but not in the adenylyl cyclase activity assay (1:5). Altogether, these data indicate that drug-drug interactions between JWH-018 and JWH-073 are effect- and ratio-dependent and may increase the relative potency of marijuana substitutes for subjective Δ9-THC-like effects. Combinations may improve the therapeutic profile of cannabinoids, considering that analgesia, but not hypothermia or task disruption, was potentiated. Importantly, synergy in the competition receptor binding assay suggests multiple CB1R-SCB binding sites.
KEYWORDS:
analgesia, cannabinoids, drug abuse, drug discrimination, drug interactions
PMID: 23801678 [PubMed – as supplied by publisher]
DIFFERENTIAL DRUG-DRUG INTERACTIONS OF THE SYNTHETIC CANNABINOIDS JWH-018 AND JWH-073: IMPLICATIONS FOR DRUG ABUSE LIABILITY AND PAIN THERAPY.
