The role of glial cells in the experience of pain: how much is important the sex factor?

Although the understanding of pain mechanisms has significantly improved in the recent years, much more is yet to be discovered. Broadening of our knowledge is needed in order to find innovative treatments for fighting pain, mainly neuropathic pain. As a matter of fact, all current therapeutic options for neuropathic pain are unsatisfactory and commonly associated with severe side effects. We studied the complex network of interactions along the nociceptive pathways through the study of behavioral responses and immunohistochemical alterations in the expression of specific protein markers at peripheral and central level in the Chronic Constriction Injury (CCI) model of neuropathic pain in CD1 adult male and female mice. In particular, we focused our attention on the link between pain and glial function. As a matter of fact, a growing relevance of glial cells has highlighted their role in physiological and pathological processes related to pain: generation and maintenance of neuropathic pain are associated to glia activation in central and peripheral nervous system. In the spinal cord, the activation of microglia and astrocytes is accompained by morphological changes (such as hypertrophy and proliferation) as well as changes in glial markers and in signaling pathways (such as phosphorylation of mitogen-activated protein kinases). At the periphery, Schwann cells have a fundamental role in degenerative/regenerative processes after injury, removing myelin debris and promoting axonal regeneration. We observed time-dependent differences in the time-course of neuropathic pain and in the activation of glia and astrocytes, as well a fundamental role played by sex. CCI induced mechanical allodynia that gradually decreased in male mice with a complete recovery occurring 81 days post surgery. Moreover, CCI induced an activation of microglia and astrocytes that completely disappeared in male 121 days after CCI. On the contrary, in female mice both allodynia and gliosis were still present 121 days after CCI. At the periphery a different expression of important proteins associated with nerve injury and repair supported faster nerve regeneration in males than in females. In both male and female mice 17beta-estradiol resulted in analgesic effects, facilitated recovery and counteracted gliosis. Our findings provide new insights in the comprehension of neurobiological mechanisms involved in pain modulation and demonstrate the importance of the sex factor for the development of more specific and targeted therapy against neuropathic pain.