Amelioration of Neuropathic Pain by Novel Transient Receptor Potential Vanilloid 1 Antagonist AS1928370 in Rats without Hyperthermic Effect

Abstract

Transient receptor potential vanilloid 1 (TRPV1) is activated by a variety of stimulations, such as endogenous ligands and low pH, and is believed to play a role in pain transmission. TRPV1 antagonists have been reported to be effective in several animal pain models; however, some compounds induce hyperthermia in animals and humans. We discovered the novel TRPV1 antagonist (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide (AS1928370) in our laboratory. AS1928370 bound to the resiniferatoxin-binding site on TRPV1 and inhibited capsaicinmediated inward currents with an IC 50 value of 32.5 nM. Although AS1928370 inhibited the capsaicin-induced Ca 2ϩ flux in human and rat TRPV1-expressing cells, the inhibitory effect on proton-induced Ca 2ϩ flux was extremely small. In addition, AS1928370 showed no inhibitory effects on transient receptor potential vanilloid 4, transient receptor potential ankyrin 1, and transient receptor potential melastatin 8 in concentrations up to 10 M. AS1928370 improved capsaicin-induced secondary hyperalgesia and mechanical allodynia in an L5/L6 spinal nerve ligation model in rats with respective ED 50 values of 0.17 and 0.26 mg/kg p.o. Furthermore, AS1928370 alleviated inflammatory pain in a complete Freund's adjuvant model at 10 mg/kg p.o. AS1928370 had no effect on rectal body temperature up to 10 mg/kg p.o., although a significant hypothermic effect was noted at 30 mg/kg p.o. In addition, AS1928370 showed no significant effect on motor coordination. These results suggest that blockage of the TRPV1 receptor without affecting the proton-mediated TRPV1 activation is a promising approach to treating neuropathic pain because of the potential wide safety margin against hyperthermic effects. As such, compounds such as ASP1928370 may have potential as new analgesic agents for treating neuropathic pain.

Botulinum toxin type A selectivity for certain types of pain is associated with capsaicin-sensitive neurons

“…-BoNT/A and TRPV1 antagonists reduce the inflammatory and neuropathic mechanical allodynia and hyperalgesia [4,18,21,33,46,49,66]. The results are ambiguous after denervation with high dose TRPV1 agonists: some studies report the reduction of mechanical allodynia [36,60], while others do not [35].…”

“…-BoNT/A, denervation of TRPV1-expressing neurons, and TRPV1 agonists, reduce the nocifensive behavior and mechanical hyperalgesia evoked by capsaicin [5,6,24,32,49,55,59], and thermal hyperalgesia evoked by inflammatory or neuropathic pain [4,5,6,16,33,36,49,56,59,60,66].…”

Carboxyl-terminal Domain of Transient Receptor Potential Vanilloid 1 Contains Distinct Segments Differentially Involved in Capsaicin- and Heat-induced Desensitization

“…Although capsaicin is a prototypical agonist of TRPV1, capsaicin-related mechanisms do not represent every aspect of TRPV1 activity under pathophysiological conditions. Moreover, modality-specific targeting of TRPV1 induces differential expression of side effects, such as hyperthermia and distinct anti-hyperalgesic efficacy in different animal models (47,48). Therefore, delineating the details of structural mechanisms mediating modality-specific regulation may allow rationalized design of compounds targeting modality-specific activity of TRPV1 to produce stronger anti-hyperalgesia with fewer adverse side effects.…”

TRPV1 Antagonists as Analgesic Agents

“…AS1928370 alleviated inflammatory pain in a CFA model at 10 mg/kg, as well [104,115]. Importantly, the intrathecal administration of AS1928370 (30 g/body) also significantly suppressed mechanical allodynia in mice.…”

“…Other potent TRPV1 antagonists (GRC6211, PHE377 and AS1928370) appear to be devoid of any febrile reaction when administered to rodents or dogs. Indeed, AS1928370 did not increased rectal body temperature up to 10 mg/kg oral treatment, although a significant hypothermic effect was noted at 30 mg/kg [104,105].…”