Androgen receptors expressed in the primary sensory neurons regulate mechanical pain sensitivity

The expression of hormonal receptors in pain-processing regions complicates understanding the hormonal effects on pain mechanisms. This study investigates androgen receptor (AR) involvement in pain sensitivity and sex differences in pain perception. Mechanical pain thresholds were higher in normal male mice compared to gonadectomized (GDX) male and normal female mice, correlating with serum testosterone levels. In the dorsal root ganglia (DRG), AR was expressed in normal males but undetectable in GDX males and normal females. Androgen receptor overlapped with NeuN, a neuronal nuclei marker, indicating androgen signaling activation in sensory neurons. In male sensory neuron-selective AR conditional knockout (AR-cKO) mice, mechanical pain thresholds were significantly lower than in wild-type males, with the greatest AR depletion in calcitonin gene-related peptide (CGRP) + neurons. Electrophysiological analyses revealed increased excitability of spinal dorsal horn neurons in both GDX males and AR-cKO males. In female mice, administration of testosterone propionate or dihydrotestosterone significantly raised mechanical pain thresholds, accompanied by increased AR expression in the DRG. This effect was abolished in AR-cKO females, where AR depletion was most prominent in CGRP + neurons, consistent with male findings. These results indicate that primary sensory neurons, particularly CGRP + neurons, are critical targets of androgen in regulating mechanical pain sensitivity. Therefore, manipulating androgen signaling in sensory neurons may offer a promising approach to managing mechanical pain.