Abstract Cannabinoids are frequently used in the treatment of neuropathic pain related to nerve injury. However, despite evidence for their roles in the regulation of axonal guidance and synapse formation during development of the central nervous system (CNS), their possible involvement in response to peripheral nerve injury remains poorly defined and the knowledge of its role is mostly related to the peripheral sensory system. Following nerve injury, contemporary to axonal repair, massive morphological and functional changes reshape synaptic elements at neuromuscular junctions (NMJs) aiming to promote their reinnervation. This process is mediated in part by Perisynaptic Schwann cells (PSCs), glial cells at the NMJ essential for its maintenance and repair. Here we investigated the novel role of Cannabinoid type-1 receptor (CB 1 R) at NMJ, in particular on PSCs, during motor nerve recovery following nerve injury. Using morphological analysis, we studied the consequences of CB 1 R pharmacological and genetic blockade following denervation and reinnervation in adult NMJs. CB 1 R blockade caused an acceleration of the denervation process followed by a great delay in reinnervation as indicated by a significant percentage of denervated NMJs, accompanied by a decrease of mono- and poly-innervated NMJs. Remarkably, a similar phenomenon was observed when CB 1 R is selectively knocked-out in glia, indicating that the protective actions of these receptors are largely glia-dependent. These data highlight a novel role of the endocannabinoid system at NMJs, where the CB 1 Rs on PSCs can control NMJ denervation and reinnervation following nerve injury. A better understanding of the functional mechanisms underlying CB 1 R role in NMJ repair may contribute to finding a new pharmacological treatment having a dual role in improvements of motor recovery and in pain-related relief.

Cannabinoid type-1 (CB1) receptors in glial cells promote neuromuscular junction repair following nerve injury