HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity - PubMed (original) (raw)

HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity

Samer R Eid et al. Mol Pain. 2008.

Abstract

Background: Safe and effective treatment for chronic inflammatory and neuropathic pain remains a key unmet medical need for many patients. The recent discovery and description of the transient receptor potential family of receptors including TRPV1 and TRPA1 has provided a number of potential new therapeutic targets for treating chronic pain. Recent reports have suggested that TRPA1 may play an important role in acute formalin and CFA induced pain. The current study was designed to further explore the therapeutic potential of pharmacological TRPA1 antagonism to treat inflammatory and neuropathic pain.

Results: The in vitro potencies of HC-030031 versus cinnamaldehyde or allyl isothiocyanate (AITC or Mustard oil)-induced TRPA1 activation were 4.9 +/- 0.1 and 7.5 +/- 0.2 microM respectively (IC50). These findings were similar to the previously reported IC50 of 6.2 microM against AITC activation of TRPA1 1. In the rat, oral administration of HC-030031 reduced AITC-induced nocifensive behaviors at a dose of 100 mg/kg. Moreover, oral HC-030031 (100 mg/kg) significantly reversed mechanical hypersensitivity in the more chronic models of Complete Freunds Adjuvant (CFA)-induced inflammatory pain and the spinal nerve ligation model of neuropathic pain.

Conclusion: Using oral administration of the selective TRPA1 antagonist HC-030031, our results demonstrated that TRPA1 plays an important role in the mechanisms responsible for mechanical hypersensitivity observed in inflammatory and neuropathic pain models. These findings suggested that TRPA1 antagonism may be a suitable new approach for the development of a potent and selective therapeutic agent to treat both inflammatory and neuropathic pain.

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Figures

Figure 1

Figure 1

The effect of TRPA1 antagonism on _AITC_-induced nocifensive behaviors. Both 100 mg/kg (red bar) and 300 mg/kg (blue bar) of HC-030031 significantly reduced lifting behavior relative to vehicle treated rats given plantar injection of 1% AITC (white bar; * p, 0.05).

Figure 2

Figure 2

The effect of TRPA1 antagonism on complete Freund's adjuvant induced mechanical hypersensitivity. A. Paw withdrawal thresholds for the injected hind paw were assessed using the Randall-Selitto device prior to intraplantar CFA injections, prior to dosing with vehicle (white bars), 20 mg/kg naproxen (green bars), 100 mg/kg HC-030031 (red bars) or 300 mg/kg HC-030031 (blue bars), and at one hour post p.o. dosing. Naproxen, 100 mg/kg and 300 mg/kg HC-030031 produced a significant attenuation in mechanical hypersensitivity at one hour post dose (*p < 0.05). B. Paw withdrawal thresholds for the noninjected hind paw assessed using the Randall-Selitto device prior to intraplantar CFA injections, prior to dosing with vehicle (white bars), 20 mg/kg naproxen (green bars), 100 mg/kg HC-030031 (red bars) or 300 mg/kg HC-030031 (blue bars), and at one hour post p.o. dosing. C. Percent reversal seen at one hour post p.o. dosing with vehicle (white bars), 20 mg/kg naproxen (green bars), 100 mg/kg HC-030031 (red bars) or 300 mg/kg HC-030031 (blue bars).

Figure 3

Figure 3

The effect of HC-030031 on spinal nerve ligation induced mechanical hypersensitivity. A. Fifty percent paw withdrawal thresholds for the L5/L6 spinal nerve ligated rats assessed using the Dixon up/down method prior to surgery, prior to dosing with vehicle (white bars), 20 mg/kg pregabalin (green bars), 100 mg/kg HC-030031 (red bars) or 300 mg/kg HC-030031 (blue bars), and at one hour post p.o. dosing. Pregabalin and 300 mg/kg HC-030031 produced a significant attenuation in mechanical hypersensitivity at one hour post dose (*p < 0.05). B. Percent reversal seen at one hour post p.o. dosing with vehicle (white bars), 20 mg/kg pregabalin (green bars), 100 mg/kg HC-030031 (red bars) or 300 mg/kg HC-030031 (blue bars).

Figure 4

Figure 4

The effect of HC-030031 on locomotor coordination and thermal sensitivity. A. Neither the 100 mg/kg (red bar) nor the 300 mg/kg (blue bar) dose of HC-030031 had a significant impact on the latency to fall off the rotarod during locomotor testing relative to vehicle treated rats (white bar). B. HC-030031 also failed to produce a significant change in thermal latencies on the hot plate test for rats dosed at 100 mg/kg (red bar) or 300 mg/kg (blue bar) relative to vehicle treated rats (white bar).

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