Sustained potentiation by substance P of NMDA-activated current in rat primary sensory neurons

This study aimed to explore the modulatory effect of substance P (SP) on the current response mediated by N-methyl-D-aspartate (NMDA) receptor in rat primary sensory neurons and its time course using whole-cell patch clamp technique. The majority of neurons (179/213, 84.0%) examined were sensitive to NMDA (0.1-1000 μM) with an inward current, and a proportion of the NMDA-sensitive neurons also responded to SP (78/98, 80.0%) with an inward current. Pretreatment with SP potentiated the NMDA-activated current (I _NMDA) in a non-competitive manner, which is shown in that SP shifted the concentration-response curve for NMDA upwards compared with the control; the maximal value of I_NMDA increased fourfold, while the EC₅₀ values for both curves were very close (28 vs. 30 μM). Furthermore, this potentiating effect was time-dependent: the amplitude of I_NMDA reached its maximum 20 min after SP preapplication, and thereafter maintained a steady level of about 2-3 times its control for 2 or even 3 h. This sustained potentiation by SP of I_NMDA could be blocked by extracellular application of WIN51708, a selective non-peptide antagonist of NK-1 receptor; and abolished by intracellular application of either BAPTA, or H-7, or KN-93. Though NMDA applied alone also induced a short-term (less than 20 min) self-potentiation of I_NMDA, it could be abolished by intracellular dialysis of BAPTA or KN-93 completely. As is known, the cell body of dorsal root ganglion (DRG) neurons is generally used as an accessible model for studying the characteristics of the membrane of primary afferent terminals in the dorsal horn of spinal cord. Therefore, these results may offer a clue to the explanation of the symptoms of chronic pain.