Differential Drug-Drug Interactions of the Synthetic Cannabinoids JWH-018 and JWH-073: Implications for Drug Abuse Liability and Pain Therapy
Differential Drug-Drug Interactions of the Synthetic Cannabinoids JWH-018 and JWH-073: Implications for Drug Abuse Liability and Pain Therapy
复制标题
DOI：
10.1124/jpet.113.206003
复制
发表时间：
2013-09-01
影响因子：
3.5
通讯作者：
Fantegrossi, William E.
中科院分区：
文献类型：
--
作者：
Brents, Lisa K.;Zimmerman, Sarah M.;Fantegrossi, William E.
Marijuana substitutes often contain blends of multiple psychoactive synthetic cannabinoids (SCBs), including the prevalent SCBs (1-pentyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-018) and (1-butyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-073). Because SCBs are frequently used in combinations, we hypothesized that coadministering multiple SCBs induces synergistic drug-drug interactions. Drug-drug interactions between JWH-018 and JWH-073 were investigated in vivo for Delta(9)-tetrahydrocannabinol (Delta(9)-THC)-like discriminative stimulus effects, analgesia, task disruption, and hypothermia. Combinations (JWH-018: JWH-073) of these drugs were administered to mice in assays of Delta(9)-THC discrimination, tail-immersion, and food-maintained responding, and rectal temperatures were measured. Synergism occurred in the Delta(9)-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, whereas a 1: 3 dose ratio induced subadditive suppression of food-maintained responding. In vitro drug-drug interactions were assessed using competition receptor-binding assays employing mouse brain homogenates and cannabinoid 1 receptor (CB1R)-mediated inhibition of adenylyl cyclase activity in Neuro2A wild-type 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 Delta(9)-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.
