Fig. 5: In vivo characterization of C6-Quino in chronic pain states.

A Mice were subjected to chronic constriction injury (CCI), a model of neuropathic pain. They demonstrate reductions in paw withdrawal 7 days after surgery (second leftmost points). This effect was not reversed by the subcutaneous administration of the vehicle (5% DMSO/95% saline, n = 14 mice) and C6-Quino at 5 mg/kg dose (n = 8 mice). However, C6-Quino displays significant anti-allodynic effects at either 10 mg/kg (n = 9 mice) or 30 mg/kg (n = 10 mice, with 7 mice at 100 and 140 min, and 3 mice at 180 min) doses similar to a one-hour pretreatment with gabapentin administered at a 50 mg/kg dose IP (n = 11 mice). B C6-Quino (30 mg/kg, IP) shows comparable anti-hyperalgesic effects to SNC80 (10 mg/kg, IP) in the Complete Freund’s Adjuvant (CFA) model of inflammatory pain. C In the nitroglycerin-induced chronic migraine model, C6-Quino (30 mg/kg, IP) completely reversed cephalic allodynia. D C6-Quino was effective after both oral and subcutaneous administration at 30 mg/kg, with its effects blocked by the δ-opioid receptor antagonist NTB in the CCI model. E Pharmacokinetic analysis confirmed reasonable brain and plasma exposure of C6-Quino following an 80-min pretreatment. F Unlike the full δ-opioid agonist SNC80, C6-Quino (30 mg/kg, sc) did not induce convulsions. G C6-Quino, unlike morphine, did not cause hyperlocomotion. H Mice were administered either saline (n = 20), vehicle (n = 12), morphine (30 mg/kg, sc; n = 12), or C6 Quino (30 mg/kg, sc; n = 12), and the breath rate was measured every 20 min for 120 min. Morphine significantly reduced the breath rate with respect to saline at 20 min, 40 min, 60 min (****p < 0.0001) and 80 min (*p = 0.0225) post-drug administration. C6-Quino was not significantly different from vehicle control as determined by 2-way ANOVA followed by Dunnett’s multiple-comparison test. All data are represented as mean ± SEM. For detailed statistical analyses of (A–D and F, G), see Supplementary Tables 15–21.