Targeting the cholinergic system as a therapeutic strategy for the treatment of pain

doi:10.1016/j.neuropharm.2007.04.002

Neuropharmacology

Volume 53, Issue 2, August 2007, Pages 197-206

https://doi.org/10.1016/j.neuropharm.2007.04.002 Get rights and content

Abstract

Acetylcholine mediates its effects through both the nicotinic acetylcholine receptors (ligand-gated ion channels) and the G protein-coupled muscarinic receptors. It plays pivotal roles in a diverse array of physiological processes and its activity is controlled through enzymatic degradation by acetylcholinesterase. The effects of receptor agonists and enzyme inhibitors, collectively termed cholinomimetics, in antinociception/analgesia are well established. These compounds successfully inhibit pain signaling in both humans and animals and are efficacious in a number of different preclinical and clinical pain models, suggesting a broad therapeutic potential. In this review we examine and discuss the evidence for the therapeutic exploitation of the cholinergic system as an approach to treat pain.

Introduction

Acetylcholine mediates its effects through both the nicotinic acetylcholine receptors (ligand-gated ion channels) and the G protein-coupled muscarinic receptors. It plays pivotal roles in a diverse array of physiological processes and its activity is controlled through enzymatic degradation by acetylcholinesterase. The effects of receptor agonists and enzyme inhibitors, collectively termed cholinomimetics, in antinociception/analgesia are well established. These compounds successfully inhibit pain signaling in both humans and animals and are efficacious in a number of different preclinical and clinical pain models (see Table 1), suggesting a broad therapeutic potential. In this review we examine and discuss the evidence for the therapeutic exploitation of the cholinergic system as an approach to treat pain.

Section snippets

Mechanisms of cholinomimetic analgesia

A major site of action for cholinomimetics in analgesia is the spinal cord. Intrathecal cholinergic agents cause antinociception by mimicking the release of acetylcholine (ACh) from the spinal cholinergic nerves. Painful stimuli are known to increase ACh in the spinal cord, as seen in the CSF of anesthetized sheep following noxious stimulation (Eisenach et al., 1996). This ACh is released from the cholinergic interneurons in the dorsal horn, which are activated by the inhibitory descending

Acetylcholinesterase

The hydrolysis of ACh by acetylcholinesterase (AChE) has a key role in limiting the activation of both nicotinic and muscarinic receptors. Overactivity of these receptors causes a multitude of adverse physiological effects and can result in respiratory failure and death. However, cholinesterase inhibitors have shown activity in clinical trials for pain.

Muscarinic acetylcholine receptors

The slow actions of acetylcholine are mediated through the muscarinic acetylcholine receptors (mAChRs), a family of five related G protein-coupled receptors, which are expressed throughout the CNS and in peripheral tissues (Caulfield and Birdsall, 1998). M1, 3 and 5 are linked to phospholipase C via Gq and their stimulation leads to formation of inositol phosphates and a consequent increase in intracellular calcium. M2 and M4 couple through the inhibitory G protein, Gi/o and inhibit formation

Nicotinic acetylcholine receptors

The fast actions of acetylcholine are mediated by its interaction with the nicotinic acetylcholine receptors (nAChRs), a family of pentameric ligand-gated ion channels composed of one or more of sixteen different subunits (α, β, etc.) and distributed widely throughout the CNS and the periphery. In the CNS the predominant nAChRs are the homomeric α7 receptor and the heteromeric α4/β2 receptor representing α-bungarotoxin sensitive and insensitive receptors, respectively, providing a convenient

Conclusions

The cholinergic system offers a number of tractable targets for the development of pain therapeutics. We have discussed the wealth of literature suggesting that cholinomimetics have broad therapeutic potential for efficacy against a number of clinically relevant pain states including inflammatory, neuropathic, visceral pain and pain due to arthritis.

To date, efforts to produce subtype-selective agents have been largely unsuccessful representing the primary obstacle to the successful entry of an

Acknowledgement

We would like to thank Dr. Garth Whiteside, Wyeth Neurosciences, for his valuable comments on our manuscript.

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ReviewTargeting the cholinergic system as a therapeutic strategy for the treatment of pain

Abstract

Introduction

Section snippets

Mechanisms of cholinomimetic analgesia

Acetylcholinesterase

Muscarinic acetylcholine receptors

Nicotinic acetylcholine receptors

Conclusions

Acknowledgement

European Journal of Pharmacology

Brain Research

Brain Research

Brain Research

Neuropharmacology

European Journal of Pharmacology

Neuroscience Letters

Pain

Behavioural Brain Research

Brain Research

Brain Research Bulletin

Brain Research

Brain Research

Pain

European Journal of Pharmacology

Journal of Neuroimmunology

Pain

Toxicon

European Journal of Pharmacology

Brain Research

European Journal of Pharmacology

Neuropharmacology

Life Sciences

Brain Research

Neuropharmacology

Bioorganic Medincinal Chemistry Letters

Life Sciences

Pain

Neuropharmacology

Brain Research

Molecular Brain Research

Journal of Neuroimmunology

Journal of Neuroimmunology

Neuroscience

Neuroscience

Life Sciences

Pharmacology and Therapeutics

Brain Research

Low-dose intrathecal neostigmine enhanced the analgesic effect of intrathecal morphine following gynecologic surgery

Anesthesiology

Broad-spectrum, non-opioid analygesic activity by selective modulation of neuronal nicotinic acetylcholine receptors

Science

ABT-594 [(R)-5-2(azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective antinociceptive agent acting via neuronal nicotinic acetylcholine receptors: II. in vivo characterization. Journal of Pharmacology and Experimental

Therapeutics

Sex difference in pain

Behavioural Brain Sciences

Rat dorsal root ganglia express M1–M4 muscarinic receptor proteins

Journal of the Peripheral Nervous System

Excitatory nicotinic and desensitizing muscarinic (M2) effects on C-nociceptors in isolated rat skin

Journal of Neuroscience

Muscarinic M2 receptors on peripheral nerve endings: a molecular target of antinociception

Journal of Neuroscience

Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin

Nature

Postoperative analgesia from intrathecal neostigmine in sheep

Anesthesia and Analgesia

Characterization of a rat model of incisional pain

Pain

Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2-exo-2-(2′,3′-disubstituted 5′-pyridinyl)-7-azabicyclo[2.2.1]heptanes: epibatidine analogues

Journal of Medicinal Chemistry

Review
Targeting the cholinergic system as a therapeutic strategy for the treatment of pain