Functional crosstalk between neuropeptide FF system and N-type voltage-gated calcium channels in ziconotide-mediated antinociception in mice.

Ziconotide is a selective, potent, and reversible blocker of neuronal N-type voltage-gated calcium channels (VGCCs). Neuropeptide FF (NPFF) belongs to the opioid-modulating peptide family and plays a vital role in pain control through interactions with the opioid system. NPFF receptor agonists inhibit N-type VGCCs via G-protein coupling mechanism. This study focuses on whether intrathecal administration of NPFF influences ziconotide-induced antinociception. The effects of NPFF and related peptides on the antinociceptive activities of ziconotide were examined in male Kunming mice. Results showed that NPFF significantly enhanced ziconotid-induced analgesia in a dose-dependent manner in both the mouse tail-flick test and the visceral pain model. Additionally, treatment with the NPFF receptor selective antagonist RF9 markedly reduced the ziconotide-modulating effects of NPFF and related peptides in the pain models, whereas treatment with the opioid receptors antagonist naloxone had no effect. Co-administration of ziconotide with NPFF and related peptides from day 1 to day 8 produced insignificant differences in analgesic sensitivity, indicating that NPFF and related peptides did not induce tolerance to ziconotide following chronic co-treatment. These data provide the first in vivo evidence of a functional interaction between the NPFF system and N-type VGCCs, demonstrating that spinal NPFF receptor activation interferes with ziconotide-mediated antinociception. Thus, combining ziconotide with NPFF agonists may represent a valuable strategy for pain management.