In vivo effects of synthetic cannabinoids JWH-018 and JWH-073 and phytocannabinoid Δ9-THC in mice: inhalation versus intraperitoneal injection

Abstract

Human users of synthetic cannabinoids (SCBs) JWH-018 and JWH-073 typically smoke these drugs, but preclinical studies usually rely on injection for drug delivery. We used the cannabinoid tetrad and drug discrimination to compare in vivo effects of inhaled drugs with injected doses of these two SCBs, as well as with the phytocannabinoid Δ(9)-tetrahydrocannabinol (Δ(9)-THC). Mice inhaled various doses of Δ(9)-THC, JWH-018 or JWH-073, or were injected intraperitoneally (IP) with these same compounds. Rectal temperature, tail flick latency in response to radiant heat, horizontal bar catalepsy, and suppression of locomotor activity were assessed in each animal. In separate studies, mice were trained to discriminate Δ(9)-THC (IP) from saline, and tests were performed with inhaled or injected doses of the SCBs. Both SCBs elicited Δ(9)-THC-like effects across both routes of administration, and effects following inhalation were attenuated by pretreatment with the CB1 antagonist/inverse agonist rimonabant. No cataleptic effects were observed following inhalation, but all compounds induced catalepsy following injection. Injected JWH-018 and JWH-073 fully substituted for Δ(9)-THC, but substitution was partial (JWH-073) or required relatively higher doses (JWH-018) when drugs were inhaled. These studies demonstrate that the SCBs JWH-018 and JWH-073 elicit dose-dependent, CB1 receptor-mediated Δ(9)-THC-like effects in mice when delivered via inhalation or via injection. Across these routes of administration, differences in cataleptic effects and, perhaps, discriminative stimulus effects, may implicate the involvement of active metabolites of these compounds.

Keywords: Antinociception; Behavior; Cannabinoids; Drug discrimination; Hypothermia; Locomotor activity.

Fig. 1

Effects of JWH-018 (filled circles), JWH-073 (open squares), and Δ⁹-THC (filled triangles) on rectal temperature after intraperitoneal injection (left) or inhalation (center), and comparison of effect-scaled doses of inhaled Δ⁹-THC (100 mg/30 L), JWH-018 (10 mg/30 L) and JWH-073 (30 mg/30 L) on rectal temperature with (open bars) and without (filled bars) 3 mg/kg rimonabant pretreatment (right). “Air” indicates data obtained from mice placed in the inhalation chamber and exposed to the fan and room air only, while “EtOH” indicates data obtained from mice placed in the inhalation chamber and exposed to combustion of nitrocellulose paper previously treated with the 100% EtOH solution used to dissolve the cannabinoids. Data points in dose-effect curves represent mean ± SEM, and absence of error bars indicate instances where the variability is contained within the point See Results section for statistical comparisons. Bars indicate mean ± SEM, and asterisks indicate significant differences from vehicle-treated EtOH controls by one-way ANOVA and Dunn's test.

Fig. 2

Effects of JWH-018 (filled circles), JWH-073 (open squares), and Δ⁹-THC (filled triangles) on locomotor activity after intraperitoneal injection (left) or inhalation (center), and comparison of effect-scaled doses of inhaled Δ⁹-THC, JWH-018 and JWH-073 on motor activity with (open bars) and without (filled bars) rimonabant pretreatment (right). All other graph properties as described in Fig. 1.

Fig. 3

Effects of JWH-018 (filled circles), JWH-073 (open squares), and Δ⁹-THC (filled triangles) on tail flick latency after intraperitoneal injection (left) or inhalation (center), and comparison of effect-scaled doses of inhaled Δ⁹-THC, JWH-018 and JWH-073 on motor activity with (open bars) and without (filled bars) rimonabant pretreatment (right). All other graph properties as described in Fig. 1.

Fig. 4

Effects of JWH-018 (filled circles), JWH-073 (open squares), and Δ⁹-THC (filled triangles) on horizontal bar catalepsy after intraperitoneal injection (left) or inhalation (right). Since no cataleptic effects were observed after inhaled cannabinoids, no tests were performed in the presence of rimonabant pretreatment. All other graph properties as described in Fig. 1.

Fig. 5

Cataleptic effects of maximal doses of injected Δ⁹-THC (left) and JWH-018 (middle) yielded similar quantitative data, but the appearances of animals in each condition were qualitatively distinct. All mice injected with JWH-018 exhibited rigid posture and profound leg splay in the hindlimbs, full-body twitches, and handling-induced convulsions, but these effects were not observed following injection of Δ⁹-THC, even in animals displaying the maximum possible catalepsy score of 30s. Leg splay, twitches and convulsions were blocked in mice treated with 3 mg/kg rimonabant prior to JWH-018 (right, and see Table 1).

Fig. 6

Δ⁹-THC-like discriminative stimulus effects of JWH-018 (filled circles) and JWH-073 (open circles), after inhalation (left) or intraperitoneal injection (right). All other graph properties as described in Fig. 1.