cAmbly, a peptide derived from the star tick Amblyomma sculptum salivary gland transcriptome, attenuates inflammatory pain by activating endogenous opioid pathways.

Pain affects more than 1.5 billion people worldwide and remains a leading cause of disability, but currently available analgesics often have limited efficacy and significant adverse effects. In this context, bioactive molecules derived from animal venoms and secretions have emerged as promising novel therapeutic agents. Here, we investigated the antinociceptive and anti-inflammatory properties of cAmbly, a cell-penetrating peptide derived from the C-terminal region of Amblyomin-X, a protein from the salivary gland transcriptome of the Amblyomma sculptum tick. In cultured human sensory-like neurons exposed to an advanced glycation end products (AGEs)-induced pro-nociceptive environment, cAmbly reduced substance P release, increased β-endorphin levels, and restored neurite outgrowth. Proteomic analysis further indicated that these effects mediated by MAPK-related signaling pathways are involved in neuronal sensitization and inflammatory responses. Consistent with these findings, cAmbly reduced capsaicin-induced calcium flux in cultured rat dorsal root ganglion (DRG) neurons, an effect reversed by the opioid antagonist naloxone. Importantly, in in vivo assays, cAmbly reduced pain-like behavior in models of formalin-induced acute nociception and CFA-induced persistent inflammatory pain, and the systemic treatment decreased TNF-α, IL-6, CXCL1, and CCL2 levels in inflamed paw tissues. The antinociceptive effects were reversed by naloxone, confirming the involvement of endogenous opioid pathways. Together, these findings demonstrate that cAmbly attenuates nociceptive signaling in sensory neurons and inflammatory responses through an endogenous opioid-dependent mechanism, highlighting its potential as a novel therapeutic candidate for pain management.