Glycine Receptor Subtypes and Their Roles in Nociception and Chronic Pain

Abstract

Disruption of the inhibitory control provided by the glycinergic system is one of the major mechanisms underlying chronic pain. In line with this concept, recent studies have provided robust proof that pharmacological intervention of glycine receptors (GlyRs) restores the inhibitory function and exerts anti-nociceptive effects on preclinical models of chronic pain. A targeted regulation of the glycinergic system requires the identification of the GlyR subtypes involved in chronic pain states. Nevertheless, the roles of individual GlyR subunits in nociception and in chronic pain are yet not well defined. This review aims to provide a systematic outline on the contribution of GlyR subtypes in chronic pain mechanisms, with a particular focus on molecular pathways of spinal glycinergic dis-inhibition mediated by post-translational modifications at the receptor level. The current experimental evidence has shown that phosphorylation of synaptic α1β and α3β GlyRs are involved in processes of spinal glycinergic dis-inhibition triggered by chronic inflammatory pain. On the other hand, the participation of α2-containing GlyRs and of β subunits in pain signaling have been less studied and remain undefined. Although many questions in the field are still unresolved, future progress in GlyR research may soon open new exciting avenues into understanding and controlling chronic pain.

Molecular determinants of tetrahydrocannabinol binding to the glycine receptor

“…Specifically, GlyRs mediate a fast synaptic transmission between neurons acting as inhibitory channels: Upon ligand binding, these receptors permit the flow of chloride ions across the cell membrane, provoking a hyperpolarization of the cell and a consequent decrease in cellular excitability. This feature is of particular interest in the adult spinal cord dorsal horn, where GlyRs are abundantly expressed, since they mediate inflammatory pain sensation 6,7 . In this sense, it has been stablished that pharmacological intervention on GlyRs exerts anti‐nociceptive effects in preclinical models of chronic pain 8 …”

“…This feature is of particular interest in the adult spinal cord dorsal horn, where GlyRs are abundantly expressed, since they mediate inflammatory pain sensation. 6,7 In this sense, it has been stablished that pharmacological intervention on GlyRs exerts anti-nociceptive effects in preclinical models of chronic pain. 8 GlyRs are pentameric LGICs (Figure 1B) composed of combinations of five types of subunits (α1-α4 and β) in the format of α-homopentamers or α/β-heteropentamers.…”

“…The usual arrangement described for heteropentamers is either three α and two β or two α and three β subunits, 9,10 with a recently reported configuration of four α and one β. 11 The roles of individual GlyR subunits in nociception are diverse, 7 but expanding evidence points toward a fundamental contribution of α3-containing GlyRs. 12 GlyRs-α3 are highly expressed in the substantia gelatinosa of the spinal dorsal horn, where primary afferent nociceptive nerve fibers make synaptic connections.…”

Case report: A case of anti-glycine receptor encephalomyelitis triggered by post-transplant or COVID-19 infection?

“…GlyR expression is also observed in GABAergic synapses within certain hippocampal interneurons and pyramidal neurons ( 9 ). The presence of GlyR autoantibody hinders GlyR activity and invariably leads to motor dysfunction ( 10 ) and pain ( 11 ). Despite numerous previous studies linking GlyR antibodies to SPS/PERM ( 1 ), the range of diseases related to GlyR antibodies varies greatly.…”

Pain modulation in the spinal cord

“…The circuitry of the spinal cord is, therefore, very complex, and we need to recognize and understand this. Indeed, while presynaptic inhibition does occur, it is we now appreciate, less of a controller than postsynaptic inhibition, and that both inhibition and excitation have multiple different feed forward and feedback elements ( 9 – 12 ). Finally, in addition to the expanded understanding of the nature and dynamics of the sensory inflow generated in highly specialized sensory neurons and the multiple different circuits they activate in the dorsal horn, we also now recognize that non-neuronal cells (glia and microglia) have an active role in generating pain-triggering processes in the spinal cord ( 13 , 14 ), something not featured in the gate control theory.…”