TRPA1 Modulation of Spontaneous and Mechanically Evoked Firing of Spinal Neurons in Uninjured, Osteoarthritic, and Inflamed Rats

Abstract

BackgroundThere is growing evidence supporting a role for TRPA1 receptors in the neurotransmission of peripheral mechanical stimulation. In order to enhance understanding of TRPA1 contributions to mechanotransmission, we examined the effects a selective TRPA1 receptor antagonist, A-967079, on spinal neuronal activity following peripheral mechanical stimulation in uninjured, CFA-inflamed, and osteoarthritc (OA) rats.ResultsSystemic injection of A-967079 (30 μmol/kg, i.v.) decreased the responses of wide dynamic range (WDR), and nociceptive specific (NS) neurons following noxious pinch stimulation of the ipsilateral hind paw in uninjured and CFA-inflamed rats. Similarly, A-967079 reduced the responses of WDR neurons to high-intensity mechanical stimulation (300 g von Frey hair) of the knee joint in both OA and OA-sham rats. WDR neuronal responses to low-intensity mechanical stimulation (10 g von Frey hair) were also reduced by A-967079 administration to CFA-inflamed rats, but no effect was observed in uninjured rats. Additionally, the spontaneous activity of WDR neurons was decreased after A-967079 injection in CFA-inflamed rats but was unaltered in uninjured, OA, and OA-sham animals.ConclusionsBlockade of TRPA1 receptors disrupts transmission of high-intensity mechanical stimulation to the spinal cord in both uninjured and injured rats indicating that TRPA1 receptors have an important role in noxious mechanosensation in both normal and pathological conditions. TRPA1 receptors also contribute to the transmission of low-intensity mechanical stimulation, and to the modulation of spontaneous WDR firing, but only after an inflammatory injury.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…In vitro, A-967079 is more potent for human TRPA1 (IC 50 = 67 nM) than rat TRPA1 (IC 50 = 290 nM) and demonstrates good oral bioavailability . In preclinical studies, A-967079 inhibited spontaneous and mechanically evoked firing of spinal wide dynamic range and nociceptive-specific neurons in OA rats (McGaraughty et al, 2010). Janssen Pharmaceuticals described two lead compound series: 1) highly potent biaryl pyrimidines that contain a pyrrolidine carboxamide side chain, and 2) compounds based on the tricyclic thioxodihydroindenopyrimidinone core (see Strassmeier and Bakthavatchalam, 2011).…”

Mouse Monoclonal Antibodies to Transient Receptor Potential Ankyrin 1 Act as Antagonists of Multiple Modes of Channel Activation

“…Trevisani et al (2007) previously reported that excess accumulation of reactive oxygen species produced at inflammatory sites leads to the production of reactive chemicals, such as 4-ONE, a product of lipid peroxidation. Previous reports indicate that these products of lipid peroxidation activate TRPA1 and may contribute to inflammatory pain behavior in rodent models of inflammation (McMahon and Wood, 2006;McGaraughty et al, 2010;Lapointe and Altier, 2011). To evaluate the ability of the antagonist mAbs to block TRPA1 activation by reactive lipid peroxidation products, we first determined the EC 90 values for 4-ONE, 4-HNE, and 4-hydroxyhexenal in their concentration-dependent curves of 45 Ca 21 uptake into CHO-TRPA1 cells.…”

Molecular Basis Determining Inhibition/Activation of Nociceptive Receptor TRPA1 Protein

“…Systemic injection of A967079 decreases spontaneous and mechanically evoked firing of spinal neurons in uninjured, osteoarthritic, and inflamed rats (43). Oral administration of A967079 to rats decreases the AITCinduced nociceptive response and osteoarthritic pain (21).…”