Loss of STEP ₆₁ couples disinhibition to N-methyl-d-aspartate receptor potentiation in rodent and human spinal pain processing

Abstract

Dysregulated excitability within the spinal dorsal horn is a critical mediator of chronic pain. Dedek et al. report that downregulation of tyrosine phosphatase STEP ₆₁ links disinhibition to NMDAR potentiation in human and rodent spinal pain processing, and develop an ex vivo human preclinical model to help bridge the translational divide.

Abstract

Dysregulated excitability within the spinal dorsal horn is a critical mediator of chronic pain. In the rodent nerve injury model of neuropathic pain, BDNF-mediated loss of inhibition (disinhibition) gates the potentiation of excitatory GluN2B N-methyl- d-aspartate receptor (NMDAR) responses at lamina I dorsal horn synapses. However, the centrality of this mechanism across pain states and species, as well as the molecular linker involved, remain unknown. Here, we show that KCC2-dependent disinhibition is coupled to increased GluN2B-mediated synaptic NMDAR responses in a rodent model of inflammatory pain, with an associated downregulation of the tyrosine phosphatase STEP ₆₁. The decreased activity of STEP ₆₁ is both necessary and sufficient to prime subsequent phosphorylation and potentiation of GluN2B NMDAR by BDNF at lamina I synapses. Blocking disinhibition reversed the downregulation of STEP ₆₁ as well as inflammation-mediated behavioural hypersensitivity. For the first time, we characterize GluN2B-mediated NMDAR responses at human lamina I synapses and show that a human ex vivo BDNF model of pathological pain processing downregulates KCC2 and STEP ₆₁ and upregulates phosphorylated GluN2B at dorsal horn synapses. Our results demonstrate that STEP ₆₁ is the molecular brake that is lost following KCC2-dependent disinhibition and that the decrease in STEP ₆₁ activity drives the potentiation of excitatory GluN2B NMDAR responses in rodent and human models of pathological pain. The ex vivo human BDNF model may thus form a translational bridge between rodents and humans for identification and validation of novel molecular pain targets.