Abstract
BACKGROUND AND PURPOSE: The voltage-gated sodium channel Na(V) 1.7 is considered a therapeutic target for pain treatment based on human genetic evidence. GpTx-1 and its potent analogue [Ala(5) , Phe(6) , Leu(26) , Arg(28) ]GpTx-1 (GpTx-1-71) were recently characterized as Na(V) 1.7 inhibitors in vitro. Furthermore, the present work was conducted to investigate the analgesic properties of these two peptides in different pain models after spinal administration. EXPERIMENTAL APPROACH: The antinociceptive activities of both GpTx-1 and GpTx-1-71 were investigated in mouse models of acute, visceral, inflammatory and neuropathic pain. Furthermore, the side effects of GpTx-1 and GpTx-1-71 were evaluated in rotarod, antinociceptive tolerance, acute hyperlocomotion and gastrointestinal transit tests. KEY RESULTS: The i.t. administration of both GpTx-1 and GpTx-1-71 dose-dependently produced powerful antinociception in the different pain models. This effect was attenuated by the opioid receptor antagonist naloxone, suggesting the involvement of the opioid system. In this study, repeated administration of these two_peptides produced spinal analgesia without a loss of potency over 8 days in mouse models of acute, inflammatory and neuropathic pain. Moreover, spinal administration of GpTx-1 and GpTx-1-71 did not induce significant effects on motor coordination, evoke acute hyperlocomotion or increase gastrointestinal transit time. CONCLUSIONS AND IMPLICATIONS: Our data indicate that the Na(V) 1.7 peptide inhibitors GpTx-1 and GpTx-1-71 produce powerful, nontolerance-forming analgesia in preclinical pain models, which might be dependent on the endogenous opioid system. In addition, at the spinal level, the limited side effects imply that these Na(V) 1.7 peptide inhibitors could be potentially developed as GpTx-1-based drugs for pain relief.