ANTAGONISM OF NOCICEPTIVE RESPONSES OF CAT SPINAL DORSAL HORN NEURONSIN-VIVO BY THE NK-1 RECEPTOR ANTAGONISTS CP-96,345 AND CP-99,994, BUTNOT BY CP-96,344

Extracellular and intracellular studies were undertaken to test the ef fects of the non-peptide, substance P (NK-1) receptor antagonists CP-9 6,345 and CP-99,994, and of CP-96,344, the inactive enantiomer of CP-9 6,345, on the responses of spinal dorsal horn neurons to peripheral no xious and non-noxious cutaneous stimuli in spinalized cats anesthetize d with alpha-chloralose. The effect of these agents on the response of dorsal horn neurons to iontophoretic application of substance P was a lso tested in extracellular studies. The substance P-induced slow, pro longed discharge of dorsal horn neurons was blocked by administration (0.5 mg/kg, i.v.) of CP-96,345 (n = 10) or CP-99,994 (n = 9), but was unaffected by CP-96,344 (n = 9). The response of substance P-sensitive neurons to noxious thermal stimulation of the cutaneous receptive fie ld, especially the late afterdischarge phase, was also significantly i nhibited by CP-96,345 (n = 10) and by CP-99,994 (n = 7). The response of such neurons to noxious pinch stimulation of the receptive field wa s also significantly inhibited by CP-96,345 (n = 7) and CP-99,994 (n = 8), but the response of three other substance P-sensitive neurons to pinch was unaffected by CP-96,345. CP-96,344 did not affect the respon se of any neuron tested to either of these noxious stimuli (noxious th ermal, n = 7; pinch, n = 6). The response to hair afferent stimulation was unaffected by any of these compounds (CP-96,345, n = 16; CP-96,34 4, n = 5; CP-99,994, n = 6). In intracellular studies, the effect of t hese antagonists was tested on responses of dorsal horn neurons to nox ious pinch stimulation or to a train of high intensity electrical stim ulation of the superficial peroneal nerve. Both stimuli produced an in itial fast depolarization followed by a slow and prolonged depolarizat ion with corresponding discharge patterns. CP-96,345 (n = 3) and CP-99 ,994 (n = 6) selectively blocked the late, slow components of the stim ulus-evoked response without affecting the early components. Responses to single electrical pulses of the same intensity and duration were n ot affected. CP-96,344 did not affect any of the responses tested (n = 5). The data indicate that nociceptive responses of a subset of spina l dorsal horn cells are selectively blocked by the NK-1 receptor antag onists, CP-96,345 and CP-99,994, thus confirming the involvement of NK -1 receptors in these responses. As CP-96,344 did not affect any of th e responses, it is likely that some of the properties common to CP-96, 345 and CP-96,344, such as blockade of calcium channels, may not play a significant role in the selective antagonism of nociceptive response s by these non-peptide antagonists.