Enhanced expression of spinal PTP1B contributes to peripheral inflammation- induced glycinergic disinhibition and mechanical pain.

Spinal glycinergic disinhibition represents an important contributor to mechanical pain hypersensitivity. However, the molecular mechanisms through which peripheral inflammation induces glycinergic disinhibition remain incompletely understood. Here we show that the protein tyrosine phosphatase-1B (PTP1B) is present at inhibitory synapses of spinal somatostatin-positive (SOM+) interneurons, a key subpopulation of mechanosensory neurons that conveys nociceptive information. PTP1B directly binds to and dephosphorylates the glycine receptor α1 subunit (GlyR α1). Peripheral inflammation-induced hyperexpression of PTP1B competitively interrupts the interaction of GlyR α1 with GPR39, leading to glycinergic disinhibition, enhanced excitatory output of SOM+ interneurons, and behavioral hypersensitivity. Pharmacological activation of GPR39, however, could disrupt the PTP1B-GlyR α1 interaction and resume GPR39 binding, resulting in reinstated glycinergic inhibition. Our findings uncover the important role of PTP1B in glycinergic disinhibition following peripheral inflammation and suggest a mechanistic model for dynamic regulation of glycinergic transmission by alternative interactions of GlyR α1 with PTP1B and GPR39.