Different receptor mechanisms underlying phytocannabinoid‐ versus synthetic cannabinoid‐induced tetrad effects: Opposite roles of CB₁/CB₂ versus GPR55 receptors

Abstract

Background and Purpose Cannabis or cannabinoids produce characteristic tetrad effects—analgesia, hypothermia, catalepsy and suppressed locomotion, which are believed to be mediated by the activation of cannabinoid CB1 receptors. Given recent findings of CB2 and GPR55 receptors in the brain, we examined whether these receptors are also involved in cannabinoid action. Experimental Approach We compared Δ9‐tetrahydrocannabinol (Δ9‐THC)‐, WIN55212‐2‐, or XLR11‐induced tetrad effects between wild‐type (WT) and each genotype of CB1‐, CB2‐ or GPR55‐knockout (KO) mice and then observed the effects of antagonists of these receptors on these tetrad effects in WT mice. Key Results Systemic administration of Δ9‐THC, WIN55212‐2 or XLR11 produced dose‐dependent tetrad effects in WT mice. Genetic deletion or pharmacological blockade of CB1 receptors abolished the tetrad effects produced by all three cannabinoids. Unexpectedly, genetic deletion of CB2 receptor abolished analgesia and catalepsy produced by Δ9‐THC or WIN55212‐2, but not by XLR11. Microinjections of Δ9‐THC into the lateral ventricles also produced tetrad effects in WT, but not in CB1‐KO mice. CB2‐KO mice displayed a reduction in intraventricular Δ9‐THC‐induced analgesia and catalepsy. In contrast to CB1 and CB2 receptors, genetic deletion of GPR55 receptors caused enhanced responses to Δ9‐THC or WIN55212‐2. Antagonisim of CB1, CB2 or GPR55 receptors produced alterations similar to those observed in each genotype mouse line. Conclusions and Implications These findings suggest that in addition to CB1, both CB2 and GPR55 receptors are also involved in some pharmacological effects produced by cannabinoids. CB1/CB2, in contrast to GPR55, receptors appears to play opposite roles in cannabinoid action.

Review of delta‐8‐tetrahydrocannabinol (Δ8‐THC): Comparative pharmacology with Δ9‐THC

“…This effect may be due to the regulation of extracellular dopamine release in the nucleus accumbens (Li et al, 2021). CB 2 -null mice also have a different response to some tetrad tests compared with wild-type mice, particularly the analgesic and catalepsy tests (Liu et al, 2017(Liu et al, , 2020Wang et al, 2020).…”

Explication of CB1 receptor contributions to the hypothermic effects of Δ9-tetrahydrocannabinol (THC) when delivered by vapor inhalation or parenteral injection in rats

“…Effects of THC on temperature appear to mostly be mediated via the CB 1 receptor since the CB 1 antagonist/inverse agonists SR141716 (Rimonabant) and AM-251 have been shown to block effects of cannabinoid agonists such as ∆ 9 -tetrahydrocannabinol (THC) when delivered by parenteral injection (Grim et al, 2017;Taffe et al, 2015) and deletion of the CB 1 receptor in mice prevents hypothermic responses to THC (Wang et al, 2019;Zimmer et al, 1999). Prior studies from this laboratory found that SR141716, administered 15 minutes prior to intraperitoneal injection of THC blocked the body temperature decreases, and tail-flick latency increases (Nguyen et al, 2016b;Taffe et al, 2015;, which is consistent with prior reports that SR141716 pretreatment attenuated a prolactin response to THC (Fernandez-Ruiz et al, 1997) and the hypothermia caused by the CB 1 full agonist WIN 55,212-2 in mice (Son et al, 2010).…”

Mepirapim, a Novel Synthetic Cannabinoid, Induces Addiction-Related Behaviors through Neurochemical Maladaptation in the Brain of Rodents

“…The open field test (OFT) was performed to determine whether Mepirapim treatment induces hypomotility. The test used previously reported experimental designs, with minor modifications [36]. The open field was an opaque plastic box (30 × 30 × 30 cm), divided into 16 (4 × 4) equal sectors (7.5 × 7.5 cm).…”

“…Body temperature ( • C) measurements were taken, with minor modifications of previously reported experimental designs, to determine whether Mepirapim treatment induces hypothermia [36]. After the basal body temperature was measured, mice were treated with the drug.…”