The Influence of Individual Resistance Training Variables on Muscle Strength: A Systematic Review and Meta-analysis.

Peripheral inflammation and nerve injury result in spinal sensitization and nociceptive hypersensitivity. One typical sensory symptom is mechanical pain hypersensitivity that manifests as an increased sensitivity to innocuous mechanical stimuli or movement. According to the gate control theory of pain, spinal nociceptive transmission is gated by GABAergic or glycinergic inhibitory interneurons in the dorsal horn. Under physiological conditions, these inhibitory interneurons are activated by the primary afferent low-threshold mechanoreceptors (LTMRs) and act to reduce the pain transmission from mechanosensory interneurons to projection neurons. As a representative population of mechanosensory interneurons, the somatostatin-positive (SOM) excitatory neurons play a crucial role in the conveyance of mechanosensory information. Following tissue or nerve injury, spinal GABAergic or glycinergic disinhibition allows LTMR input to activate SOM interneurons. However, the cellular and molecular mechanisms of the glycinergic disinhibition remain incompletely understood. G protein-coupled receptor 39 (GPR39) belongs to the ghrelin/neurotensin receptor family with a high degree of constitutive activities toward Gαq/11, Gα12/13, and Gαs proteins. Accumulating evidence indicates that GPR39 engages multiple G protein signaling pathways to modulate synaptic strength and neuronal excitability, and its dysregulation is implicated in several psychiatric disorders. Activation of GPR39 in the spinal cord alleviates neuropathic and chronic inflammatory pain. A recent study shows that a substantial pool of GPR39 is located in inhibitory synapses of spinal SOM neurons, where it directly interacts with glycine receptor α1 subunit (GlyR α1) and positively regulates glycinergic transmission in a G protein-independent manner. Pharmacological activation of GPR39 or enhancement of the GPR39-GlyR α1 interaction alleviates mechanical pain behaviors via potentiating glycinergic transmission, but the molecular mechanism remains to be revealed. Phosphorylation modification is a crucial regulatory mechanism for ion channel function and is involved in diverse biological and pathological processes. GlyR α1 is found to harbor putative phosphorylation residues that are implicated in the activity-dependent modification of glycinergic efficacy. The tyrosine phosphorylation at Tyr339 within the intracellular large loop of GlyR α1 is a key event that required for glycinergic transmission. Multiple protein tyrosine phosphatases (PTPs) have been found in spinal cord dorsal horn, but the exact roles of PTPs in regulating glycinergic transmission remain to be elucidated. Here, we identified a specific interaction of protein tyrosine phosphatases-1B (PTP1B) with GlyRs, and revealed a mechanistic pattern for the dynamic regulation of glycinergic transmission. Our data showed that PTP1B and GPR39 competitively interacted with GlyR α1 to regulate the tyrosine phosphorylation of GlyR α1 and glycinergic inhibition. Pharmacological activation of GPR39 reversed glycinergic disinhibition and alleviated mechanical pain via disrupting the PTP1B-GlyR α1 interaction in complete Freund’s adjuvant (CFA)-induced inflammation pain and spared nerve injury (SNI)-induced neuropathic pain model.