Stimulating Glial Gq-Coupled GPCR Pathways Blocks Acute Pain and Itch

Minton, Suzanne Kurtzer

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March 21, 2019

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Minton, Suzanne Kurtzer
- Affiliation: School of Medicine, Department of Pharmacology

Abstract

Glial G protein-coupled receptor (GPCR) pathways have been linked to synaptic modulation. However, their roles in pain and itch processing are unknown and have been difficult to study because glia and neurons often express overlapping GPCRs. The transgenic mouse model glial fibrillary acidic protein-Designer Receptor Exclusively Activated by a Designer Drug (GFAP-DREADD) is a useful model for selectively stimulating Gq-GPCR pathways on GFAP-positive cells. Gq-DREADD is expressed in astrocytes, but not neurons, in the spinal cord. Imaging studies demonstrated that Gq-DREADD stimulation causes calcium increases in astrocytes in lamina II and V of the spinal cord in slices from Gq-DREADD mice but not in those from wild-type mice. Stimulating Gq-DREADD caused a long-lasting antinociceptive phenotype for Gq-DREADD mice but not for wild-type mice as measured using the Hargreaves test. Selective stimulation of spinal cord and DRG Gq-DREADD was sufficient to mediate this effect. Surprisingly, removal of the IP3R2 receptor did not affect Gq-DREADD-mediated antinociception, suggesting that stimulation of GFAP-positive Gq-GPCR pathways can inhibit pain transmission in an IP3R2-independent manner. C-fos has been used as a marker of neuronal activity in response to noxious stimuli. Gq-DREADD stimulation did not alter the ability of noxious stimuli to induce c-fos in the dorsal horn. Nociceptors make their central projections in the dorsal horn, and a decrease in excitatory neurotransmission at this synapse would be antinociceptive. We examined this hypothesis by performing dorsal root stimulation experiments and found that Gq-DREADD stimulation did not modulate evoked field potentials in lamina II. The neurocircuitry that is used in pain processing has a large degree of overlap with itch-sensitive neurocircuitry. Gq-DREADD stimulation was also shown to block histamine-dependent itch, and this phenotype appears to be peripherally mediated. Collectively, our experiments indicate that Gq-GPCR pathways in GFAP-positive glia can be antinociceptive in the setting of acute pain and can mediate antinociception in an IP3R2-independent manner. In addition, Gq-GPCR pathways in astrocytes can block acute itch. These data provide insight into the roles that glial Gq-GPCR pathways play in the modulation of acute pain and itch, which may lead to the development of novel therapies for chronic pain and itch neuropathies.

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