Background: Excessive inflammation and fibrosis during wound healing can cause delayed repair and pathological scar formation. This study aimed to investigate the effects of butorphanol on inflammation and fibrosis during wound healing and to explore the underlying molecular mechanisms.

Methods: A rat burn wound model was established and treated with varying doses of butorphanol. Wound closure rates were recorded on days 3, 7, 10, and 14 post-injury. Histological analyses were performed to assess tissue repair and fibrosis. Expression levels of pro-inflammatory cytokines, macrophage polarization markers, fibrosis-related proteins, and p38/c-Jun N-terminal kinase (JNK) signaling molecules were measured using real-time quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry, and Western blotting. Pharmacological inhibitors and agonists targeting the interleukin-6 (IL-6)/p38/JNK pathway were applied to validate mechanistic involvement.

Results: Butorphanol significantly accelerated wound healing, reduced inflammatory cell infiltration, and downregulated pro-inflammatory cytokines in the early stages (p < 0.05). It promoted macrophage polarization toward the anti-inflammatory M2 phenotype by increasing Cluster of Differentiation (CD)206 expression and suppressing CD86 expression (p < 0.05). Temporally, butorphanol enhanced the early expression of fibrosis-associated markers to support the transition to the proliferative phase, while suppressing their excessive late-stage expression to prevent pathological scarring (p < 0.05). Mechanistically, butorphanol inhibited activation of the IL-6/p38/JNK signaling pathway, as evidenced by altered pathway activity following pharmacological modulation, thereby regulating inflammation and fibrosis during healing (p < 0.05).

Conclusion: Butorphanol promotes orderly wound healing by modulating inflammation and fibrosis through regulation of the IL-6/p38/JNK signaling axis. These findings establish butorphanol as a promising therapeutic candidate for enhancing burn wound repair, and offer new perspectives on the IL-6/p38/JNK axis as a potential molecular target for regulating inflammation and fibrosis.