Sex-specific involvement of calcitonin gene–related peptide signaling for pain in experimental autoimmune encephalomyelitis

Abstract Introduction: Neuropathic pain (NP) is one of the most devastating and under-managed symptoms of multiple sclerosis (MS). As it stands, NP is a difficult condition to treat, as many commonly used pain therapies are ineffective. Research has now emerged demonstrating sex differences in the mechanism of NP in MS, adding complexity to the search for new treatments. Although it is widely known that female patients are more likely than male patients to develop MS, it is less commonly acknowledged that they are also more likely to experience NP in the disease. Thus, there is an urgent need to develop NP treatments specifically for female patients with MS. Methods: Using the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, we have characterized the outgrowth in culture as well as the spinal innervation pattern of peptidergic primary sensory afferents in both sexes. We then used a receptor antagonist to disrupt neuropeptide signaling from these cells to treat pain. Results: We found structural plasticity in peptidergic nociceptors from female animals with established EAE both in vitro and in vivo, as well as increased antibody stain intensity for the neuropeptide calcitonin gene–related peptide (CGRP). Using a receptor antagonist for CGRP (CGRP8-37), we were able to reverse spontaneous pain in female EAE animals. Conclusions: These results suggest that targeting peptidergic nociceptors and CGRP signaling, specifically in female patients, may be a viable strategy to relieve and possibly reverse pain in female patients with MS.