Sex and dose-dependent antinociceptive effects of the JNK (c-Jun N-terminal kinase) inhibitor SU 3327 are mediated by CB2 receptors in female, and CB1/CB2 receptors in male mice in an inflammatory pain model

Abstract

Activation of c-Jun N-terminal kinases (JNKs) has been implicated in the development and persistence of inflammatory and neuropathic pain in animal models. Moreover, JNKs have been involved in the maintenance of chronic pain, as well as development of tolerance to antinociceptive agents in the opioid and cannabinoid class of compounds. In this study, we evaluated the antinociceptive effects of the JNK inhibitor SU 3327 (0.3-30 mg/kg) in the formalin pain model with an emphasis on the sex-specific actions of this compound. In wild-type C57BL6J mice, SU 3327 produced strong antinociceptive effects in the formalin pain model which were mediated by CB₂ receptors in females, and both CB₁ and CB₂ receptors in males. SU 3327 at a dose of 10 mg/kg produced antinociception, hypothermia, motor impairment, and hypolocomotion to a similar extent in both males and females. The antinociceptive effects of SU 3327 were more potent in males at lower doses (1 and 3 mg/kg), while females were more sensitive to the hypothermic, and motor-suppression effects at lower (3 mg/kg) doses versus males. Analysis of spinal cords, using qPCR following SU 3327 administration in the formalin test, revealed changes in cannabinoid, tolerance and inflammatory markers in females only, and only in the high (10-30 mg/kg) dose conditions. Indeed, females showed an increase in mRNA levels of cannabinoid (CB₂), but a decrease in tolerance (β-arrestin 1) and inflammatory (TNF-α, IL-1β, IL-6)-associated markers. The differences between males and females, in this study, support sex as an important factor in nociception and antinociceptive responses mediated by JNK and the endocannabinoid system.

Keywords: Anti-inflammatory; Cannabinoid; Opioids; SU 3327 (Halicin); Sex-differences; Tolerance.