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.

<p>Intraneural Application of microRNA-1 Mimetic Nucleotides Does Not Resolve Neuropathic Pain After Chronic Constriction Injury in Rats</p>

“…Especially connexins are known for playing a crucial role in the pathogenesis of neuropathic pain. 24 As already shown, miR-1 levels are significantly downregulated in the peripheral nerve after inducing neuropathy via CCI. 9 Correspondingly, its targets Cx43 and BDNF were found to be upregulated, 9 implicating a negative correlation of miR-1 levels and Cx43 expression levels.…”

Pharmaceutical and Botanical Management of Pain Associated with Psychopathology: A Narrative Review

“…One of the Cxs, Cx43, is expressed in astrocytes at the level of the central and peripheral nervous system. This has been studied in animal models and related to the genesis and maintenance of chronic pain, so it could be a promising therapeutic target for future treatments that act as Cx43-gap junction blockers, at the level of the trigeminal ganglion and the sciatic nerve [51].…”

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“…So another possibility would be to do a knockdown of Cx36 in the CCI-IoN model with silencing RNA specific for Cx36. Doing a knockdown would probably reduce the adverse side effects [8].…”

“…But as stated above, a pharmacological approach might not be enough to target the specific causes of neuropathic pain. Therefore, more focused and directed research that aims to unravel the mechanisms of this pathology could lead to more effective and permanent treatments [8].…”