Role of connexins in chronic pain and their potential as therapeutic targets for next-generation analgesics

Abstract

Chronic pain, including inflammatory, neuropathic pain, is a serious clinical issue. There are increasing numbers of patients with chronic pain due to the growing number of elderly and it is estimated that about 25% of the global population will develop chronic pain. Chronic pain patients are refractory to medications used to treat acute pain such as opioids and non-steroidal anti-inflammatory drugs. Furthermore, the complexity and diversity of chronic pain mechanisms hinder the development of new analgesics. Thus, a better understanding of the mechanism of chronic pain is needed, which would facilitate the development of novel analgesics based on novel mechanisms. With this goal, connexins (Cxs) could be targeted for the development of new analgesics. Connexins are proteins with 20 subtypes, and function as channels, gap junctions between cells, and hemichannels that sample the extracellular space and release molecules such as neurotransmitters. Furthermore, Cxs could have functions independent of channel activity. Recent studies have shown that Cxs could be crucial in the induction and maintenance of chronic pain, and modulation of the activity or the expression of Cxs ameliorates nociceptive hypersensitivity in multiple chronic pain models. This review will cite novel findings on the role of of Cxs in the nociceptive transduction pathway under the chronic pain state and antinociceptive effects of various molecules modulating activity or expression of Cxs. Also, the potential of Cx modulation as a therapeutic strategy for intractable chronic pain will be discussed.