We evaluated the effects of Tetrascorpin-1 from Androctonus australis (AaTs-1), a tetrapeptide obtained from scorpion venom, previously hypothesized to bind the formyl peptide receptor like-1 (FPRL-1) known as formyl peptide receptor-2 (FPR-2) in vitro, on pain responses and cytokines, neuronal and glial morpho-functional alterations in the spinal cord of mice with formalin-induced long-lasting pain hypersensitivity. Due to the peptide chemical nature and for favoring its penetration into the central nervous system, AaTs-1 was daily administered intranasally for 10 days. In formalin-injected mice the AaTs-1 treatment abolished mechanical allodynia, thermal hyperalgesia, hyperactivation of spinal nociceptive-specific (NS) neurons, and partially restored spinal anti-inflammatory/pro-inflammatory cytokine levels and microglia/astrocyte phenotype alterations. Additionally, in contrast to what occurred in formalin-injected mice, AaTs-1 treatment facilitated the firing activity of NS neurons and consistently altered the levels of some spinal cytokines under investigation in healthy mice. Based on the opposing effects of AaTs-1 under physiological and pathological conditions, we suspect that it acts as a partial agonist in vivo rather than as an antagonist of FPR-2, as other in vitro data would suggest.
