The Selective CB2 Agonist COR167 Reduced Symptoms in a Mice Model of Trauma-Induced Peripheral Neuropathy through HDAC-1 Inhibition

Abstract

Neuropathic pain is a chronic disabling condition with a 7–10% of prevalence in the general population that is largely undertreated. Available analgesic therapies are poorly effective and are often accompanied by numerous side effects. Growing evidence indicates cannabinoids are a valuable treatment opportunity for neuropathic pain. The endocannabinoid system is an important regulator of pain perception through the CB1 receptors, but CB1 agonists, while largely effective, are not always satisfactory pain-relieving agents in clinics because of their serious adverse effects. Recently, several CB2 agonists have shown analgesic, anti-hyperalgesic, and anti-allodynic activity in the absence of CB1-induced psychostimulant effects, offering promise in neuropathic pain management. The aim of this study was to evaluate the anti-neuropathic activity of a novel selective CB2 agonist, COR167, in a preclinical model of peripheral neuropathy, the spared nerve injury (SNI). Oral COR167, in a dose-dependent manner, attenuated mechanical allodynia and thermal hyperalgesia after acute and repeated administration, showing the absence of tolerance induction. At anti-neuropathic doses, COR167 did not show any alteration in the locomotor behavior. SNI mice showed increased microglial levels of HDAC1 protein in the ipsilateral side of the spinal cord, along with NF-kB activation. COR167 treatment prevented the HDAC1 overexpression and the NF-kB activation and increased the levels of the anti-inflammatory cytokine IL-10 through a CB2-mediated mechanism. Oral administration of COR167 shows promising therapeutic potential in the management of neuropathic pain conditions.

Antinociceptive Effects of Cannabichromene (CBC) in Mice: Insights from von Frey, Tail-Flick, Formalin, and Acetone Tests

“…This finding is comparable to the time courses of other minor cannabinoids, including CBD and CBG [17,18], suggesting CBC has a similar pharmacokinetic profile [47]. Additionally, it suggests that CBC activates receptors/channels involved in mechanical hypersensitivity, potentially including TRPA1 receptors and CB2 receptors [48][49][50][51][52][53][54][55][56].…”

Potential mechanisms of exercise for relieving inflammatory pain: a literature review of animal studies

“…Adenylate cyclase and MAPK are negatively and positively connected to the CB1 and CB2 that comprise the eCB system, respectively ( Dos Santos et al, 2019 ). Several CB2 agonists exhibit analgesic, antinociceptive and antiabnormal pain activity in the absence of CB1-induced psychostimulant effects ( Borgonetti et al, 2023 ). Exercise induces the spinal release of eCBs (anandamide), which activates CB2 receptors, decreases microglial expression and the secretion of pro-inflammatory substances.…”

The Use of Compounds Derived from Cannabis sativa in the Treatment of Epilepsy, Painful Conditions, and Neuropsychiatric and Neurodegenerative Disorders

“…THC acts as a CB 1 and CB 2 agonist [ 295 ]. Activation of these receptors can lead to the reduction of neuropathic pain signs such as allodynia and hyperalgesia [ 296 ]. CBD inhibits enzymes FAAH and MAGL responsible for endocannabinoid degradation, elevating endocannabinoid levels and leading to pain relief [ 109 , 297 , 298 ].…”