Neurokinin 1 and 2 antagonists attenuate the responses and NK1 antagonists prevent the sensitization of primate spinothalamic tract neurons after intradermal capsaicin

Abstract

1. Activation of neurokinin receptors contributes to the excitation of many dorsal horn neurons by cutaneous sensory stimuli, particularly noxious stimuli. In the present study we investigate the role of neurokinin receptors in the activation of primate spinothalamic tract (STT) neurons by cutaneous mechanical stimuli and by intradermal injection of capsaicin. This was done by testing the responses of these neurons to a battery of cutaneous stimuli before and during infusion by microdialysis of antagonists selective for NK1 and NK2 receptors. 2. The NK1 receptor antagonists cis-3-(2-methoxybenzyl-amino-2-benzhydrylquinuclidine (CP96345) and D-Pro9-[Spiro-y-lactam]-Leu10,Trp11)-Physalaemin(1-11) (GR82334) did not significantly reduce the responses of STT cells to mechanical stimulation of the skin. Both NK1 antagonists did, however, produce a significant reduction in the responses of STT neurons to an intradermal injection of capsaicin. Finally, despite having no effects on responses to mechanical stimuli, both NK1 antagonists prevented the sensitization of the responses to cutaneous stimuli that is usually observed after intradermal injections of capsaicin. 3. The NK2 selective antagonists PhCO-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (GR98400) and [Tyr5,D-Trp6,8,9,Lys10]-NKA (4-10) (MEN10376) had effects very similar to those of the NK1 antagonists, but with an important difference. Neither NK2 antagonist affected the responses of STT neurons to noxious or innocuous mechanical stimulation of the skin, but they did reduce the responses to intradermal capsaicin injections. These compounds failed to prevent capsaicin-induced sensitization. In fact, cells exposed to GR98400 or MEN10376 showed unusually sustained increases in the responses to mechanical stimuli after the first capsaicin injection, suggesting that these compounds actually induced sensitization. 4. These results support the contention that both neurokinin receptors participate in the processing of nociceptive information in the dorsal horn, especially responses to strong stimuli such as intradermal injection of capsaicin. NK1 receptors are also involved in the sensitization of STT neurons after peripheral injury. A clearer understanding of the role of NK2 receptors in sensitization requires further studies with improved antagonists.

Unravelling the Mystery of Capsaicin: A Tool to Understand and Treat Pain

“…Dougherty and Willis (1992) gave intradermal capsaicin to monkeys and showed 1) that discharge rate of second-order neurons in the DH increased after injection and 2) an increase in release of the excitatory amino acids glutamate and aspartate. They also found an increase in activation of NK1 receptors on second-order neurons, which, they hypothesized, might be contributing to the sensitization (Dougherty et al, 1994).…”

Role of neurokinin type 1 receptor in nociception at the periphery and the spinal level in the rat

“…48 Blockade of spinal NK1r not only attenuated spinothalamic neuron activation following capsaicin injection in the paw but also prevented sensitization to post-capsaicin mechanical stimuli. 49 Similarly, multibarrel electrode recording form dorsal horn neurons showed that the activity of SP-sensitised dorsal horn neurons receiving afferent noxious input from the periphery was reduced by specific NK1 r antagonist-the study reports on the critical role played by SP and NK1r in pain from joints. 50 Recently, the intrathecal SP-saporin complex has been observed to relieve facet joint pain and bone cancer pain.…”

Modulation of plateau properties in dorsal horn neurones in a slice preparation of the turtle spinal cord.

“…Interestingly, recent studies have shown that CP96345 (a non-peptide NK-1 receptor antagonist) has anti-nociceptive effects in the formalin and capsaicin tests (Sakurada, Katsumata, Yogo, Tan-No, Sakurada & Kisara, 1993). Although this drug also has antagonist effects on Ca2P channels (Schmidt, McLean & Heym, 1992) the involvement of the NK-1 receptor in nociceptive mechanisms is supported by results based on the specific antagonist GR 82334 (Dougherty, Palecek, Paleckova & Willis, 1994). Metabotropic glutamate receptors are thought to play a role in modulation of synaptic transmission and neuronal excitability in the brain and contribute to regulate neuronal networks (Pin & Duvoisin, 1995) including nociceptive circuits in the spinal cord (Meller, Dykstra & Gebhart, 1993;Young, Fleetwood-Walker, Mitchell & Munro, 1994;Boxall, Thompson, Dray, Dickenson & Urban, 1996).…”