Activation of neurokinin-1 receptors increases the excitability of guinea pig dorsal root ganglion cells.
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 μm) dissociated L6 and S1 dorsal root ganglion (DRG) neurons from female guinea pigs. Current-clamp recording revealed that Sar-Met-SP (1 μM) elicited membrane depolarization (average 8.05 ± 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 = 35 neurons), 2) a prolongation of AP duration (from 4.64 to 5.29 ms, n = 34), and 3) a reduction in the maximal rate of AP repolarization. NTP (200 nM) reversed the Sar-Met-SP-induced changes. Ca(2+) imaging showed that application of Sar-Met-SP (1 μM) decreased the tachyphylaxis induced by repeated application of capsaicin (0.5 μM), 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.
Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania, USA. xiz50@pitt.edu
Xiulin
X
Zhang
Claudio
C
Pietra
Emanuela
E
Lovati
William C
WC
de Groat
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006168:Guinea Pigs; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D064729:Neurokinin-1 Receptor Antagonists; D011725:Pyridines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000378:metabolism*; D013373:Substance P / Q000494:pharmacology; D010879:Piperazines; D044482:Benzeneacetamides
D064729:Neurokinin-1 Receptor Antagonists; D011725:Pyridines; D018040:Receptors, Neurokinin-1; D013373:Substance P; C508854:netupitant; D010879:Piperazines; D044482:Benzeneacetamides