Behavioral and Molecular Basis of Cholinergic Modulation of Pain: Focus on Nicotinic Acetylcholine Receptors
Nicotinic acetylcholine receptors (nAChRs) have emerged as a novel therapeutic strategy for pain and inflammatory disorders. In particular, α4β2∗, α7, and α9α10 nAChR subtypes have been investigated as potential targets to treat pain. The nAChRs are distr
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Contents 1 Introduction 2 nAChRs in Pain Modulation 3 The α4β2 nAChRs in Pain Modulation 4 The α7 nAChRs in Pain Modulation 5 The α9/α9α10 nAChRs in Pain Modulation 6 Conclusions References
Abstract Nicotinic acetylcholine receptors (nAChRs) have emerged as a novel therapeutic strategy for pain and inflammatory disorders. In particular, α4β2, α7, and α9α10 nAChR subtypes have been investigated as potential targets to treat pain. The nAChRs are distributed on the pain transmission pathways, including central and peripheral nervous systems and immune cells as well. Several agonists for α4β2 nAChR subtypes have been investigated in multiple animal pain models with promising results. However, studies in human indicated a narrow therapeutic window for α4β2 agonists. Furthermore, animal studies suggest that using agonists
W. Toma, E. Ulker, and M. I. Damaj (*) Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA e-mail: [email protected] M. Alqasem Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia S. D. AlSharari Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia J. M. McIntosh Departments of Psychiatry and Biology, University of Utah, Salt Lake City, UT, USA © Springer Nature Switzerland AG 2020 Curr Topics Behav Neurosci https://doi.org/10.1007/7854_2020_135
W. Toma et al.
for α7 nAChR subtype and antagonists for α9α10 nAChR subtypes are potential novel therapies for chronic pain management, including inflammatory and neuropathic pain. More recently, alternative nAChRs ligands such as positive allosteric modulators and silent agonists have shown potential to develop into new treatments for chronic pain. Keywords Inflammatory pain · Neuropathic pain · Nicotinic acetylcholine receptors · α4β2 nAChRs · α7 nAChR · α9α10 nAChRs
1 Introduction Effective and safe treatment of pain remains one of the most significant challenges in medicine. Pain affects more than 100 million Americans (Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education 2011) at the cost of greater than $635 billion a year (Gaskin and Richard 2012). The current opioid crisis, partly fueled by prescription opioids for pain control, has highlighted the enormous challenge to the medical community of managing chronic pain. Relatively few options are available for therapy, including nonsteroidal antiinflammatory drugs (NSAIDs), steroids, opioids, gabapentinoids, reuptake inhibitors, and local anesthetic agents. Each of these classes of drugs possesses varying degrees of clinical efficacy in specific patient groups, and all are associated with untoward side effects that undermine utility. There is an urgent need to discover new drugs to treat acute and chronic pain that are effective and also safe. While over the last several years, there has been a major push in the identification
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