Figure 8: Consequences of spinal TRPA1 activation.

TRPA1 is expressed on the central terminals of primary sensory neurons in the dorsal horn of the spinal cord. Activation of TRPA1, for example, by electrophilic metabolites of APAP, increases the influx of calcium, which causes inactivation of voltage-gated calcium channels (VGCC)^35,36. Cation influx through TRPA1 also depolarizes the membrane and produces a sustained inhibition of voltage-gated sodium channels (NaV), thereby reducing neuronal excitability and action potential-dependent neurotransmitter release. The net result of these actions is inhibition of C-fibre-evoked postsynaptic excitation, although TRPA1-mediated calcium influx may initially increase spontaneous excitatory postsynaptic currents via activation of ionotropic glutamate receptors (iGluR)^42,49,50,51. Similar molecular mechanisms have been advanced to explain the antinociceptive effect of spinal TRPV1 activation^31,48.