ANTAGONISM OF NOCICEPTIVE RESPONSES OF CAT SPINAL DORSAL HORN NEURONS IN VIVO BY THE NK-1 RECEPTOR ANTAGONISTS CP-96,345 AND CP-99,994, BUT NOT BY CP-96,344

Abstract Extracellular and intracellular studies were undertaken to test the effects of the non-peptide, substance P (NK-1) receptor antagonists CP-96,345 and CP-99,994, and of CP-96,344, the inactive enantiomer of CP-96,345, on the responses of spinal dorsal horn neurons to peripheral noxious and non-noxious cutaneous stimuli in spinalized cats anesthetized with α-chloralose. The effect of these agents on the response of dorsal horn neurons to iontophoretic application of substance P was also tested in extracellular studies. The substance P-induced slow, prolonged 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 field, especially the late afterdischarge phase, was also significantly inhibited 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 was 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 response of any neuron tested to either of these noxious stimuli (noxious thermal, n = 7; pinch, n = 6). The response to hair afferent stimulation was unaffected by any of these compounds (CP-96,345, n = 16; CP-96,344, n = 5; CP-99,994, n = 6). In intracellular studies, the effect of these antagonists was tested on responses of dorsal horn neurons to noxious pinch stimulation or to a train of high intensity electrical stimulation of the superficial peroneal nerve. Both stimuli produced an initial fast depolarization followed by a slow and prolonged depolarization with corresponding discharge patterns. CP-96,345 ( n = 3) and CP-99,994 ( n = 6) selectively blocked the late, slow components of the stimulus-evoked response without affecting the early components. Responses to single electrical pulses of the same intensity and duration were not affected. CP-96,344 did not affect any of the responses tested ( n = 5). The data indicate that nociceptive responses of a subset of spinal dorsal horn cells are selectively blocked by the NK-1 receptor antagonists, 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 the 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 responses by these non-peptide antagonists.