Muscarinic Pain Pharmacology: Realizing the Promise of Novel Analgesics by Overcoming Old Challenges

Abstract

The antinociceptive and analgesic effects of muscarinic receptor ligands in human and nonhuman species have been evident for more than half a century. In this review, we describe the current understanding of the roles of different muscarinic subtypes in pain modulation and their mechanism of action along the pain signaling pathway, including peripheral nociception, spinal cord pain processing, and supraspinal analgesia. Extensive preclinical and clinical validation of these mechanisms points to the development of selective muscarinic agonists as one of the most exciting and promising avenues toward novel pain medications.

The Analgesic Effects of (5R,6R)6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1] Octane on a Mouse Model of Neuropathic Pain

“…7 Both genetic and pharmacologic approaches have been used to study the involvement of mAChRs in the modulation of nociception. 8 Significant antinociceptive effects were observed after the administration of cholinesterase inhibitors or agonists of mAChRs in basic research studies. 8,9 Detailed information was obtained using genetic knock-out approaches on the subtypes of mAChRs, such as M2 and M4.…”

“…8,9 Detailed information was obtained using genetic knock-out approaches on the subtypes of mAChRs, such as M2 and M4. 8 Therefore, the mAChRs have been proposed as promising targets for developing novel analgesic agents.…”

Pharmacological evaluation underlying the antinociceptive activity of two new hybrids NSAIDs tetrahydropyran derivatives

“…The activation of muscarinic receptors induces the release of several modulators and regulates the permeability of various ion channels, which in this way are responsible for the control in the transmission of pain. Some studies report the analgesic properties of cholinergic agonists in animal experiments involving stimulation of the cholinergic pathway through the activation of spinal muscarinic receptors .…”

The Centrally-Mediated Mechanisms of Action of Ferulic Acid–Induced Antinociception

“…Descending pain pathways are one of the most important pain control systems. The mechanism of descending inhibition and supraspinal/spinal signal integration includes the release of a number of neurotransmitters, particularly endogenous opioids, noradrenaline, serotonin, and acetylcholine, and their activity (19). Thus, the involvement of these modulatory systems in ferulic acid-induced analgesia was investigated.…”