Exploring the actions of TRPV1 positive allosteric modulators in a peripheral inflammation model

Small molecule pharmacological therapies focused on peripheral ion channels such as the transient receptor potential vanilloid-1 (TRPV1) may provide a novel therapy solution for patients in moderate to severe chronic pain. Previous studies in our lab have begun to characterize small molecule positive allosteric modulators (PAMs) of TRPV1 for pain relief. Like a potent, selective TRPV1 agonist such as resiniferatoxin (RTX), a TRPV1 PAM will act to induce calcium cytotoxicity in a clinically relevant sub-population of A-delta and C-fibers. Unlike RTX however, a TRPV1 PAM can be administered systemically since its effect relies on activity dependent vanilloid activation. To better understand its effect in an animal model of inflammation and hyperalgesia, we administered MRS1477 in combination with the TRPV1 agonist capsaicin to selectively deactivate nerves in the hindpaw. After 24 hours, we administered 4% carrageenan intraplantar (i.pl.). Behavioral experiments performed following carrageenan revealed increased paw withdrawal latency in response to thermal stimulation of the hindpaw compared to rats receiving capsaicin without MRS1477. Inactivation of TRPV1+ nerve endings by the combination of MRS1477 and capsaicin is consistent with the idea of a PAM mediated potentiation mechanism. These behavioral results indicate that a TRPV1 PAM in combination with a TRPV1 agonist may be useful in reducing nocifensive behaviors in an inflammatory pain model in rats and suggests that further investigation of TRPV1-PAM mechanisms may lead to new insights into the function of this ligand-gated ion channel. Supported by DIR, NIDCR.