Central TRPA1 Inhibition is Superior to Peripheral in Alleviating DPN and OA Pain in Rats

Background & Aims

TRPA1 gain-of-function variants are found to drive human pain (1-3). TRPA1 mRNA expression on relevant cells in the pain pathway support its role as a channel for pain in human and rodents (4-17). Also TRPA1 agonistic compounds generated under chronic pain conditions have pro-nociceptive and pro-inflammatory effects in animal models and in diabetic patients (18-23). However, previous preclinical studies combined often with no or limited pharmacokinetics indicate variable analgesic efficacy of structurally distinct TRPA1 antagonists in animal pain models (24-30). Further, recent TRPA1 antagonist clinical trials studying LY3526318 failed to show clinically meaningful analgesia (31-33). Here we hypothesize that the site of action plays a critical role in analgesic efficacy of TRPA1 antagonists. We studied the primary pharmacology, pharmacokinetics and compared pharmacodynamic effects of peripheral inhibition to central inhibition with novel TRPA1 antagonists in DPN and OA pain in rats.

Methods

Diabetic neuropathic pain was induced by i.p. Streptozotocin injection in male Wistar rats. Anti-hypersensitivity effect with Von Frey filament up-down test to estimate the 50% threshold for hindpaw withdrawal was studied either after single or repeated oral doses of novel centrally acting TRPA1 antagonists or clinically studied LY3526318 (33, n=10-11/group) in suspension on days 14 up to 24 following STZ.
Intra-articular knee MIA injection in rats induces symptoms displayed by OA patients. Analgesic efficacy of novel centrally penetrating and putative poorly CNS penetrating TRPA1 antagonists, including LY3526318 (n=10/group), in suspension after single oral doses was studied 19 days following MIA injection (= established, neuropathic-type phase) in female Wistar rats by using the Von Frey filament up-down test. Orally administered Pregabalin was used as a model reference compound in both models.

Results

Here, LY3526318 was potent in whole-cell manual patch-clamp recordings, but PK evaluation revealed that it is a very poorly CNS penetrating in rats.
CNS penetrant structurally distinct novel TRPA1 inhibitors developed by Orion resulted in a significant, even full reversal of mechanical hypersensitivity after single/repeated dosing at established phase following STZ already at unbound brain exposures ? ~IC50 concentration recorded in vitro, whereas peripheral inhibition did not.
CNS penetrant novel TRPA1 inhibitor attenuated statistically significantly mechanical hypersensitivity at neuropathic phase following MIA after single dose. Analgesia was observed at unbound brain concentrations near the IC90 concentration recorded in vitro. Neither LY3526318 nor our peripherally restricted novel TRPA1 inhibitor showed efficacy at unbound plasma concentrations reaching even the IC92-IC94 concentrations recorded in vitro.

Conclusions

Central TRPA1 inhibition reversed the STZ -induced mechanical hypersensitivity whereas peripheral inhibition did not. OA pain treatments can only reduce the pain with about 20%. Interestingly, our central TRPA1 inhibitor alleviated mechanical hypersensitivity with about ?15% in 60% of rats with chronic joint pain. Moreover, neither LY3526318 (33) nor our peripherally restricted novel TRPA1 antagonist showed efficacy in rat MIA model. Our data support the idea that central TRPA1 block over peripheral may be more efficient mechanism to alleviate DPN and OA pain. This is an intriguing finding in view of recent clinical trial results with TRPA1 blocker LY3526318 which failed to show significant pain reduction in DPN and OA (31,32). Central TRPA1 inhibition possesses untapped potential as an effective pain treatment for OA and DPN.

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Presenting Author

Niina Jalava

Poster Authors

Niina Jalava

MSc

Orion Pharma

Lead Author

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