The role of cannabinoid CB1 receptors in the antinociceptive and reparative actions of mesenchymal stem cells in rats with peripheral neuropathic pain

Mesenchymal stem cells (MSCs) can produce antinociceptive and reparative effects. Presumably, the MSCs-induced antinociception may be partly due to the involvement of the endocannabinoid system. The study aimed to evaluate the antinociceptive and reparative effects of adipose-derived MSCs (ADMSCs) upon pharmacological modulation of cannabinoid CB₁ receptor in peripheral tissues or on ADMSCs' membranes in a rat model of peripheral neuropathy. ADMSCs were injected into the area of rat sciatic nerve injury (i) with no additional treatments, (ii) at the tissue CB₁ receptor activation by endogenous agonist anandamide (AEA) or blockade with a selective AM251 antagonist; and (iii) preincubated with AEA or AM251. The evaluation of CB₁ receptor activity involved analyzing nociceptive responses, gait parameters, and histology. Transplantation of ADMSCs upon activation of CB₁ receptors, both on AMSCs' membranes or in the area of nerve injury, accelerated the analgesia and recovery of dynamic gait parameters, abolished static gait disturbances, and promoted the fastest nerve regeneration. Only blockade of CB₁ receptors on ADMSCs shortened ADMSCs-induced analgesia and decreased the number of preserved nerve fibers. CB₁ receptors on ADMSCs significantly contribute to their pain-relieving and tissue-repairing capabilities by stimulating the growth factors secretion and suppressing the release of pro-inflammatory cytokines. Peripheral CB₁ receptors do not significantly influence ADMSC-induced antinociception.