The Lysophosphatidylinositol Receptor GPR55 Modulates Pain Perception in the Periaqueductal Gray

Abstract

Emerging evidence indicates the involvement of GPR55 and its proposed endogenous ligand, lysophosphatidylinositol (LPI), in nociception, yet their role in central pain processing has not been explored. Using Ca 21 imaging, we show here that LPI elicits concentration-dependent and GPR55-mediated increases in intracellular Ca 21 levels in dissociated rat periaqueductal gray (PAG) neurons, which express GPR55 mRNA. This effect is mediated by Ca 21 release from the endoplasmic reticulum via inositol 1,4,5-trisphosphate receptors and by Ca 21 entry via P/Q-type of voltage-gated Ca 21 channels. Moreover, LPI depolarizes PAG neurons and upon intra-PAG microinjection, reduces nociceptive threshold in the hot-plate test. Both these effects are dependent on GPR55 activation, because they are abolished by pretreatment with antagonist. Thus, we provide the first pharmacological evidence that GPR55 activation at central levels is pronociceptive, suggesting that interfering with GPR55 signaling in the PAG may promote analgesia.

Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey

“…The effect of LPI was blocked by the GPR55 antagonist ML-193. These findings suggest that GPR55 in the LPAG/VLPAG is pronociceptive (Deliu et al, 2015). Similarly, P2X3 receptor expression in the LPAG is decreased in parallel with a reduction in pain thresholds in the chronic constriction injury model of neuropathic pain in SD rats.…”

Aberrant cardiolipin metabolism is associated with cognitive deficiency and hippocampal alteration in tafazzin knockdown mice

“…The specific role for each molecular species of lysophospholipids in the brain are only beginning to be elucidated. For example, there is evidence that PUFA-containing LPI is important for cortical lamination and neuronal migration 70,71 . Lysophosphatidylcholine maybe essential in human brain development and function because they provide a preformed phospholipid source for membrane repair and supply essential PUFA species 72,73 .…”

GPR55: a new promising target for metabolism?

“…Given its extensive distribution in the brain, GPR55 participates in a number of physiological processes that include movement coordination and motor activity (Wu et al 2013, Bjursell et al 2016, nociception (Deliu et al 2015), modulation of anxiety-like behaviors (Rahimi et al 2015), as well as energy expenditure (Bjursell et al 2016, Meadows et al 2016 (Fig. 1).…”