Extended Data Fig. 5: STING signalling in nociceptors is required for the antinociceptive effects of STING agonists.

a, Schematic showing mechanism of action of the small molecule STING inhibitors H-151 and C-176. b–d, i.t. administration of H-151 and C-176 induced transient mechanical (b, c) and cold hypersensitivity (d) in naive mice. e, DMXAA and ADU-S100 (35 nmol each, i.t.) increased paw withdrawal thresholds in STING^+/+ (gWT) but not in STING^gt/gt (gKO) mice. f, Administration of ADU-S100 (35 nmol, i.t.) did not alter paw withdrawal frequency to a low-threshold 0.16g Von Frey filament in STING^gt/gt mice. g, DMXAA and ADU-S100 increased paw withdrawal threshold in Sting^fl/fl (cWT) mice, but no significant effects were observed in Sting^fl/fl;Na_v1.8-Cre (cKO) mice. A non-statistically significant increase in withdrawal thresholds was observed at later time points (24 h, 48 h) in Sting^fl/fl;Na_v1.8-Cre mice. h, DMXAA and ADU-S100 (35 nmol each, i.t.) reduced mechanical hypersensitivity (determined by withdrawal frequency to a 0.16 g Von Frey filament) in Sting^fl/fl;Na_v1.8-Cre mice at 24 h and 48 h. i, Schematic indicating method of resiniferatoxin (RTX) treatment and the effects of STING agonists in RTX-treated mice. j, RTX increased withdrawal latency in the hotplate test (cutoff time = 40 s). k, The early (1 h, 4 h, 24 h) antinociceptive effects of DMXAA and ADU-S100 (35 nmol, i.t.) were abolished by RTX. l, The antinociceptive effects of DMXAA and ADU-S100 (35 nmol, i.t.) showed a normal time course of effects (relative to Fig. 1b) in Prkdc^scid mice, which lack mature B and T cells. m, Schematic indicating possible upstream activators of STING in sensory neurons, and proposed mechanism by which STING⁺ neurons regulate nociception through induction of cytokines and chemokines. While our data support that STING signalling in nociceptors contributes to the early antinociceptive effects of STING agonists, additional cell types including other sensory neuron populations and peripheral immune cells may also contribute to the prolonged antinociceptive effects at later time points. All data are expressed as the mean ± s.e.m. *P < 0.05; **P < 0.01; ***P < 0.001, ****P < 0.0001. Statistical comparisons were conducted with two-way ANOVA with Dunnett’s (vs. BL; b–h) or Tukey’s (k, l) post hoc tests. Comparisons between two groups (j) were conducted with two-tailed t-test. See Supplementary Information for complete sample sizes, sex, and statistical information.

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