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

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Muscarinic Receptors

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 208))

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.

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Abbreviations

4-DAMP:

4-Diphenyl-acetoxy-N-methyl-piperidine methiodide

ACh:

Acetylcholine

ALCAR:

Acetyl-l-carnitine

aODN:

Antisense oligodeoxyribonucleotide

ATP:

Adenosine triphosphate

BHK:

Baby hamster kidney

BuTAC:

[5R-(exo)]-6-[4-butylthio-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[3.2.1]-octane

CFA:

Complete Freund’s adjuvant

CGRP:

Calcitonin gene related peptide

CRPS:

Complex regional pain syndrome

DRG:

Dorsal root ganglion

EPSC:

Excitatory postsynaptic current

GABA:

Gamma-aminobutyric acid

GTPγS:

Guanosine 5′-O-[gamma-thio]triphosphate

HC-3:

Hemicolinium-3

i.c.v.:

Intracerebroventricular

i.t.:

Intrathecal

IB4:

Isolectin B4

IPSC:

Inhibitory postsynaptic current

mAChR:

Muscarinic receptor

MT-3:

Muscarinic toxin 3

MT-7:

Muscarinic toxin 7

NMS:

N-methylscopolamine

NRM:

Nucleus raphe magnus

NSAIDs:

Nonsteroidal anti-inflammatory agents

OXO:

Oxotremorine

OXO-M:

Oxotremorine methiodide

PAG:

Periaqueductal gray

PAM:

Positive allosteric modulator

PTX:

Pertussis toxin

QRT-PCR:

Quantitative real-time polymerase chain reaction

RT-PCR:

Reverse transcription polymerase chain reaction

RVM:

Rostral ventromedial medulla

SCS:

Spinal cord stimulation

siRNA:

Small interfering ribonucleic acid

STZ:

Streptozotocin

substituted TZTP:

3-3(Substituted-1,2,5-thiadiazol-4-yl)-12,5,6-tetrahydro-1-methyl pyridine

TNF:

Tumor necrosis factor

TRPV1:

Transient vanilloid receptor 1; the capsaicin receptor

TTX:

Tetrodotoxin

WT:

Wild-type

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Authors and Affiliations

  1. Vertex Pharmaceuticals Inc., 11010 Torreyana Road, San Diego, CA, 92127, USA

    Dennis F. Fiorino

  2. Aspyrian Therapeutics, Inc., 10575 Roselle Street, San Diego, CA, 92121, USA

    Miguel Garcia-Guzman

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  1. Dennis F. Fiorino
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  2. Miguel Garcia-Guzman
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Correspondence to Dennis F. Fiorino .

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  1. UHN67, Department of Pulmonary and Critical Ca, Oregon Health & Science University, SW Sam Jackson Park Road 3181, Portland, 97239, Oregon, USA

    Allison D. Fryer

  2. , Department of Pharmacology, Monash Institute of Pharmaceutical Scien, Royal Parade 381, Parkville, 3052, Victoria, Australia

    Arthur Christopoulos

  3. , Department of Pharmacology, University of Washington, Seattle, 98195-7750, Washington, USA

    Neil M. Nathanson

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Fiorino, D.F., Garcia-Guzman, M. (2012). Muscarinic Pain Pharmacology: Realizing the Promise of Novel Analgesics by Overcoming Old Challenges. In: Fryer, A., Christopoulos, A., Nathanson, N. (eds) Muscarinic Receptors. Handbook of Experimental Pharmacology, vol 208. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-23274-9_9

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