Intersectional genetics have yielded tremendous advances in our understanding of molecularly-identified subpopulations and circuits within the dorsal horn in neuropathic pain. We tested the hypothesis that spinal µ opioid receptor-expressing interneurons (Oprm1-INs) contribute to behavioral hypersensitivity and neuronal sensitization in the spared nerve injury model in mice.


We coupled the use of Oprm1 Cre transgenic reporter mice with whole cell patch clamp electrophysiology in lumbar spinal cord slices to evaluate the neuronal activity of Oprm1-INs in the spared nerve injury (SNI) model of neuropathic pain. We used a chemogenetic approach to activate or inhibit Oprm1-INs, followed by the assessment of behavioral signs of neuropathic pain.


We reveal that SNI yielded a robust neuroplasticity of Oprm1-INs. SNI reduced Oprm1 gene expression in the dorsal horn as well as the responsiveness of Oprm1-INs to the selective µ agonist DAMGO. SNI sensitized Oprm1-INs, as reflected by an increase in their intrinsic excitability (rheobase: Sham 38.62 ± 25.87 pA (n=29); SNI 18.33 ± 10.29 pA (n=29), p=0.0026) and spontaneous synaptic activity (sEPSC frequency in delayed firing neurons: sham 0.81 ± 0.67 Hz (n=14); SNI 1.74 ± 1.68 Hz (n=10), p=0.0466) and light brush-induced co-expression of the immediate early gene product, Fos in lamina I-II (%Fos/tdT+: sham 0.42 ± 0.57% (n=3); SNI 28.26 ± 1.92% (n=3), p=0.0001). Chemogenetic activation of Oprm1-INs produced mechanical hypersensitivity in uninjured mice (Saline: 2.91 ± 1.08g (n=6); CNO 0.65 ± 0.34 (n=6), p=0.0006), while chemogenetic inhibition reduced behavioral signs of mechanical hypersensitivity (Saline: 0.38 ± 0.37 g (n=6); CNO 1.05 ± 0.42 g (n=6), p=0.0052) and cold hypersensitivity (saline 6.89 ± 0.88s (n=5) vs CNO 2.31±0.52s (n=5), p=0.0017).


We conclude that nerve injury sensitizes pronociceptive mu opioid receptor-expressing interneurons in mouse dorsal horn. Non-opioid strategies to inhibit these interneurons might yield new treatments for neuropathic pain.