Antinociceptive Effects of the GPR55 Antagonist CID16020046 Injected into the Rat Anterior Cingulate Cortex

Bright N Okine,Gemma Mc Laughlin,Jessica C Gaspar,Brendan Harhen,Michelle Roche,David P Finn

doi:10.1016/j.neuroscience.2020.07.013

Bright N Okine, Gemma Mc Laughlin + Show 4 more

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https://doi.org/10.1016/j.neuroscience.2020.07.013

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Abstract

The G-protein coupled receptor, GPR55, modulates nociceptive processing. Given the expression of GPR55 in the anterior cingulate cortex (ACC), a key brain region involved in the cognitive and affective dimensions of pain, the present study tested the hypothesis that GPR55 signalling in the ACC facilitates inflammatory pain behaviour in rats. The expression of GPR55 in the ACC was confirmed by both western blotting and immunostaining, with evidence for neuronal localisation. Microinjection of the selective GPR55 antagonist CID16020046 into the ACC of adult male Sprague-Dawley rats significantly reduced second phase formalin-evoked nociceptive behaviour compared with vehicle-treated controls. CID16020046 administration was associated with a reduction in phosphorylation of extracellular signal-regulated kinase (ERK), a downstream target of GPR55 activation, in the ACC. Intra-ACC administration of CID16020046 prevented the formalin-induced increases in expression of mRNA coding for the immediate early gene and marker of neuronal activity, c-Fos, in the ipsilateral dorsal horn of the spinal cord. Intra-plantar injection of formalin reduced tissue levels of the endogenous GPR55 ligand 2-arachidonoyl-sn-glycero-3-phosphoinositol (2-AGPI) in the ACC, likely reflecting its increased release/utilisation. These data suggest that endogenous activation of GPR55 signalling and increased ERK phosphorylation in the ACC facilitates inflammatory pain via top-down modulation of descending pain control.

Highlights

The expression of GPR55 in the anterior cingulate cortex (ACC) has previously been reported (Henstridge et al, 2011), the functional relevance or contribution of GPR55 signalling in the ACC to pain processing is unknown
In view of the anatomical connectivity between the ACC and the descending pain pathway, and the recent evidence of a key role for GPR55 signalling in the periaqueductal grey (PAG) in nociceptive processing, the present study investigated whether GPR55 signalling in the ACC contributes to nociceptive responding in an animal model of inflammatory pain
The present study investigated the role of GPR55 receptor signalling in the rat ACC in formalin-evoked nociceptive behaviour and the underlying molecular mechanisms

Summary

Introduction

The expression of GPR55 in the ACC has previously been reported (Henstridge et al, 2011), the functional relevance or contribution of GPR55 signalling in the ACC to pain processing is unknown. In view of the anatomical connectivity between the ACC and the descending pain pathway, and the recent evidence of a key role for GPR55 signalling in the PAG in nociceptive processing, the present study investigated whether GPR55 signalling in the ACC contributes to nociceptive responding in an animal model of inflammatory pain

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