Activation of cannabinoid receptor 2 attenuates mechanical allodynia and neuroinflammatory responses in a chronic post‐ischemic pain model of complex regional pain syndrome type I in rats

Abstract

Complex regional pain syndrome type 1 (CRPS-I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized. Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes. In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord. Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation. We hypothesized that a CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling. We used chronic post-ischemia pain (CPIP) as a model of CRPS-I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking). Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS-I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord. MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630. Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS-I in the setting of ischemia and reperfusion injury.

The endocannabinoid‐alcohol crosstalk: Recent advances on a bi‐faceted target

“…The dopaminergic neuron‐specific deletion of the CB 2 receptors allowed providing evidence of the contribution of both CB 1 receptors and CB 2 receptors in the cannabinoid tetrad task. This is consistent with preclinical studies showing that selective CB 2 receptor agonists exert an attenuation of neuropathic pain pathways in rodent pain models and suggest that CB 2 receptors may contribute to the physical effect resulting from ECS direct (or alcohol‐evoked) activation.…”

Activation of dorsal horn cannabinoid CB2 receptor suppresses the expression of P2Y12 and P2Y13 receptors in neuropathic pain rats

“…The increased CB2 receptor expression after peripheral nerve injury is highly restricted within the lumbar spinal cord microglia [ 6 ]. Moreover, the same pattern of CB2 receptor expression was observed in the model of spinal nerve transaction, osteoarthritis, and post-ischemic pain [ 7 – 9 ]. In addition, CB2 messenger RNA (mRNA) is also present in cultured spinal cord microglia cells [ 10 ].…”

Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference

“…This is consistent with elevation in CB2Rs and gene expression in DRG neurons and satellite glial cells in a rat neuropathic pain model 39 . Other preclinical studies using selective CB2R agonists have been shown to attenuate mechanical allodynia and neuroinflammatory responses in rodent pain models suggesting that CB2Rs are intricately involved in the attenuation of inflammatory and neuropathic pain pathways 39 – 42 . Ongoing studies of the CB2Rs and their possible roles in many pathological conditions including pain of different etiologies may be more complicated than previously appreciated.…”