The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Sep 2013
Differential drug-drug interactions of the synthetic Cannabinoids JWH-018 and JWH-073: implications for drug abuse liability and pain therapy.
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 Δ(9)-tetrahydrocannabinol (Δ(9)-THC)-like discriminative stimulus effects, analgesia, task disruption, and hypothermia. ⋯ 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 Δ(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.
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J. Pharmacol. Exp. Ther. · Sep 2013
Stronger antinociceptive efficacy of opioids at the injured nerve trunk than at its peripheral terminals in neuropathic pain.
Activation of opioid receptors on peripheral sensory neurons has the potential for safe pain control, as it lacks centrally mediated side effects. While this approach often only partially suppressed neuropathic pain in animal models, opioids were mostly applied to animal paws although neuropathy was induced at the nerve trunk. Here we aimed to identify the most relevant peripheral site of opioid action for efficient antinociception in neuropathy. ⋯ Thus, opioids might not be effective against spontaneous pain, but they improve heat and mechanical hypersensitivity in neuropathy. Importantly, efficient alleviation of hypersensitivity is governed by peripheral opioid receptors at the injured nerve trunk rather than at its peripheral terminals. Identifying the primary action site of analgesics is important for the development of adequate pain therapies.