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Review
. 2008 Jan;117(1):141-61.
doi: 10.1016/j.pharmthera.2007.09.003. Epub 2007 Sep 22.

Modulation of pain transmission by G-protein-coupled receptors

Hui-Lin Pan  1 , Zi-Zhen Wu, Hong-Yi Zhou, Shao-Rui Chen, Hong-Mei Zhang, De-Pei Li
Affiliations
Review

Modulation of pain transmission by G-protein-coupled receptors

Hui-Lin Pan et al. Pharmacol Ther. 2008 Jan.

Abstract

The heterotrimeric G-protein-coupled receptors (GPCR) represent the largest and most diverse family of cell surface receptors and proteins. GPCR are widely distributed in the peripheral and central nervous systems and are one of the most important therapeutic targets in pain medicine. GPCR are present on the plasma membrane of neurons and their terminals along the nociceptive pathways and are closely associated with the modulation of pain transmission. GPCR that can produce analgesia upon activation include opioid, cannabinoid, alpha2-adrenergic, muscarinic acetylcholine, gamma-aminobutyric acidB (GABAB), groups II and III metabotropic glutamate, and somatostatin receptors. Recent studies have led to a better understanding of the role of these GPCR in the regulation of pain transmission. Here, we review the current knowledge about the cellular and molecular mechanisms that underlie the analgesic actions of GPCR agonists, with a focus on their effects on ion channels expressed on nociceptive sensory neurons and on synaptic transmission at the spinal cord level.

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Figures

Figure 1
Figure 1
Schematic depicting the distribution and interaction between primary afferent terminals and interneurons in the rat spinal dorsal horn upon stimulation of the three mAChR subtypes. Activation of the M2 subtype on the primary afferent terminals and M3 and M2/M4 subtypes on a subpopulation of interneurons inhibit glutamatergic input to dorsal horn neurons. Stimulation of M2, M3, and M4 subtypes on the somatodendritic site of GABAergic interneurons can potentiate synaptic GABA release. Furthermore, the M2 and M3 subtypes present on the somatodendritic site of glycinergic interneurons are responsible for increased glycinergic input to spinal dorsal horn neurons upon activation of mAChRs. Additionally, concurrent stimulation of mAChRs on adjacent GABAergic interneurons can attenuate glycinergic and glutamatergic input to spinal dorsal horn neurons through GABA spillover and activation of presynaptic GABAB receptors.
Figure 2
Figure 2
Schematic drawing showing the site and effectors of GPCRs in the modulation of pain transmission at the spinal cord level. Activation of GPCRs listed on the left inhibits VGCCs on the presynaptic terminal of primary afferents to reduce glutamate release. These GPCRs also activate GIRK channels on postsynaptic dorsal horn neurons to hyperpolarize the neuron. Additionally, stimulation of mAChRs potentiates the synaptic release of GABA and glycine from inhibitory interneurons to decrease the excitability of dorsal horn neurons that project to the brain. Together, these effects account for the analgesic effects of the agonists of these GPCRs. GIRK, G protein-coupled inwardly rectifying K+ channels; GPCRs, G protein-coupled receptors; mAChRs, muscarinic acetylcholine receptors; mGluRs, metabotropic glutamate receptors; VGCCs, voltage-gated Ca2+ channels.
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