Divergent Response to Cannabinoid Receptor Stimulation in High and Low Stress-Induced Analgesia Mouse Lines Is Associated with Differential G-Protein Activation

Bidirectional selection of mice for high (HA) and low (LA) swim stress-induced analgesia (SSIA) is associated with a divergent response to opioids. In the current study, we investigated whether the genetic divergence in opioid system activity between HA and LA mice also affects cannabinoid sensitivity. Additionally, we also investigated whether the endocannabinoid system mediates SSIA in these lines. Numerous reports support the existence of pharmacological and molecular interactions between the opioid and cannabinoid systems along the pain pathways, as both systems utilize the same G-protein subtype for signal transduction. Mice from both lines were treated with a non-selective CB₁/CB₂ agonist, WIN55,212-2 and their behavior was evaluated according to the tetrad paradigm assessing antinociception, catalepsy, hypothermia and locomotor activity. Surprisingly, the engagement of CB₁ receptors in SSIA was not confirmed. G-protein activation was studied in different brain regions and the spinal cord in the [³⁵S]GTPγS assay. It was shown that WIN55,212-2 produced more potent antinociception in HA than in LA mice. Also, HA mice displayed stronger cannabinoid-induced catalepsy in the bar test. However, LA mice were more sensitive to the hypothermic effect of WIN55,212-2. The intensity of behavioral responses to WIN55,212-2 was correlated with increased G-protein activation in the periaqueductal gray matter, frontal cortex, striatum and thalamus in HA mice. A weak response to WIN55,212-2 in LA mice could depend on impaired CB₂ receptor signaling. In conclusion, differences in both opioid and cannabinoid sensitivity between HA and LA mice could stem from alterations in intracellular second messenger mechanisms involving G-protein activation.