We used a mouse with deletion of exons 4, 5, and 6 of the SCN11A (sodium channel, voltage-gated, type XI, ␣) gene that encodes the voltage-gated sodium channel Na v 1.9 to assess its contribution to pain. Na v 1.9 is present in nociceptor sensory neurons that express TRPV1, bradykinin B 2 , and purinergic P2X 3 receptors. In Na v 1.9 ؊/؊ mice, the non-inactivating persistent tetrodotoxin-resistant sodium TTXr-Per current is absent, whereas TTXr-Slow is unchanged. TTXs currents are unaffected by the mutation of Na v 1.9. Pain hypersensitivity elicited by intraplantar administration of prostaglandin E 2 , bradykinin, interleukin-1␤, capsaicin, and P2X 3 and P2Y receptor agonists, but not NGF, is either reduced or absent in Na v 1.9 ؊/؊ mice, whereas basal thermal and mechanical pain sensitivity is unchanged. Thermal, but not mechanical, hypersensitivity produced by peripheral inflammation (intraplanatar complete Freund's adjuvant) is substantially diminished in the null allele mutant mice, whereas hypersensitivity in two neuropathic pain models is unchanged in the Na v 1.9 ؊/؊ mice. Na v 1.9 is, we conclude, an effector of the hypersensitivity produced by multiple inflammatory mediators on nociceptor peripheral terminals and therefore plays a key role in mediating peripheral sensitization.

Convergence Pharmaceuticals.

Approximately 28% of dorsal horn neurons (DHNs) in lamina V of the rat spinal cord generate voltage-dependent plateau potentials underlying accelerating discharges and prolonged afterdischarges in response to steady current pulses or stimulation of nociceptive primary afferent fibers. Using intracellular recordings in a transverse slice preparation of the cervical spinal cord, we have analyzed the ionic mechanisms involved in the generation and maintenance of plateau potentials in lamina V DHNs. Both the accelerating discharges and afterdischarges were reversibly blocked by Mn(2+) and enhanced when Ca(2+) was substituted with Ba(2+). The underlying tetrodotoxin-resistant regenerative depolarization was sensitive to dihydropyridines, being blocked by nifedipine and enhanced by Bay K 8644. Substitution of extracellular Na(+) with N-methyl-D-glucamine or choline strongly decreased the duration of the plateau potential. Loading the neurons with the calcium chelator BAPTA did not change the initial response but clearly decreased the maximum firing frequency and the duration of the afterdischarge. A similar effect was obtained with flufenamate, a specific blocker of the calcium-activated nonspecific cation current (I(CAN)). We conclude that the plateau potential of deep DHNs is supported by both Ca(2+) influx through intermediate-threshold voltage-gated calcium channels of the L-type and by subsequent activation of a CAN current. Ca(2+) influx during the plateau is potentially of importance for pain integration and the associated sensitization in spinal cord.

Sensory relay structures in the spinal cord dorsal horn are now thought to be active processing structures that function before supraspinal sensory integration. Dorsal horn neurons directly receive nociceptive (pain) signals from the periphery, express a high degree of functional plasticity and are involved in long-term sensitization and chronic pain. We show here that deep dorsal horn neurons (DHNs) in Wistar rats can switch their intrinsic firing properties from tonic to plateau or endogenous bursting patterns, depending upon the balance of control by metabotropic glutamate (mGlu) and GABA(B) receptors. We further show that this modulation acts on at least one common target, the inwardly rectifying potassium channel (Kir3). Finally, we found that these firing modes correspond to specific functional states of information transfer in which dorsal horn neurons can faithfully transmit, greatly enhance or block the transfer of nociceptive information.