Activation of Neurokinin-1 Receptors Increases the Excitability of Guinea Pig Dorsal Root Ganglion Cells

Abstract

The suppression of overactive bladder symptoms in patients and overactive bladder reflexes in animal models by neurokinin (NK)-1 receptor antagonists raises the possibility that these drugs target sensory neurons. This mechanism was evaluated by examining the interactions between a specific NK-1 agonist, [Sar 9 ,Met(O 2 )(11)]-substance P (Sar-Met-SP), and a potent NK-1 antagonist, netupitant (NTP), on small size (20 -30 m) dissociated L6 and S1 dorsal root ganglion (DRG) neurons from female guinea pigs. Current-clamp recording revealed that SarMet-SP (1 M) elicited membrane depolarization (average 8.05 Ϯ 1.38 mV) in 27% (18 of 65) of DRG neurons. In 74% of the remaining neurons (35 of 47) Sar-Met-SP decreased the rheobase for action potential (AP) generation and increased the response to a suprathreshold stimulus (3 times rheobase) without changing the membrane potential. Sar-Met-SP also induced changes in the action potential (AP) wave form, including 1) an increase in overshoot (average 5 mV, n ϭ 35 neurons), 2) a prolongation of AP duration (from 4.64 to 5.29 ms, n ϭ 34), and 3) a reduction in the maximal rate of AP repolarization. NTP (200 nM) reversed the Sar-Met-SP-induced changes. Ca 2ϩ imaging showed that application of Sar-Met-SP (1 M) decreased the tachyphylaxis induced by repeated application of capsaicin (0.5 M), an effect blocked by pretreatment with NTP (200 nM). These results raise the possibility that activation of NK-1 receptors in primary sensory neurons plays a role in the generation of overactive bladder and that block of NK-1 receptors in these neurons may contribute to efficacy of NK-1 antagonists in the treatment of overactive bladder symptoms.

Efficacy and safety of repeated dosing of netupitant, a neurokinin‐1 receptor antagonist, in treating overactive bladder

“…Further, TAK‐637 inhibited the spinal vesico‐vesical reflex induced by electrical stimulation of the proximal part of the pelvic nerve in spinal animals, but had no effect on carbachol or electrical field stimulation induced contraction of isolated bladder muscle strip . Netupitant has been shown to suppress acetic acid induced bladder overactivity in guinea pigs in‐vivo and inhibited the excitatory effect of [Sar(9), Met(O2)(11)]‐substance P, a specific NK‐1 agonist . Together, these results support that NK‐1 RAs inhibit the micturition reflex by acting on the spinal cord, without affecting cholinergic mechanisms and that activation of NK‐1 receptors in primary sensory neurons may play an important role in the generation of OAB.…”

Botulinum toxin B in the sensory afferent: Transmitter release, spinal activation, and pain behavior

“…It remains under debate whether DRG neurons possess functional NK1r. Rodent DRG cells can express NK1r mRNA [3; 53; 102], and SP can evoke depolarizing currents in DRG cells [53; 109]. Conversely, immunohistochemical evidence for NK1r on sensory neurons and their terminals is limited (supplemental data) [14; 54; 64; 77].…”

Mechanisms Involved in the Nociception Triggered by the Venom of the Armed Spider Phoneutria nigriventer

“…TRPV1-positive sensory fibres express NK 1 and NK 2 receptors as well as produce the selective ligands substance P and neurokinin A, which are released in response to nociceptive stimulation and may produce paracrine or autocrine effects that amplify the nociceptive process [63]. In fact, NK 1 and NK 2 receptors expressed by sensory nerves cause sensitisation of TRPV1 receptors, increase neuronal excitability and induce nociception in rodents [63], [64], [65]. We observed that a combination of NK 1 and NK 2 receptor antagonists was as efficacious as the antagonists alone to reduce PNV-induced nociception, but was less efficacious than sensory nerve ablation.…”