Neurokinin Receptors (neurokinin + receptor)

Distribution by Scientific Domains

Selected Abstracts

Excitatory actions of substance P in the rat lateral posterior nucleus

Kush Paul
Abstract The lateral posterior nucleus (LP) receives inputs from both neocortex and superior colliculus (SC), and is involved with integration and processing of higher-level visual information. Relay neurons in LP contain tachykinin receptors and are innervated by substance P (SP)-containing SC neurons and by layer V neurons of the visual cortex. In this study, we investigated the actions of SP on LP relay neurons using whole-cell recording techniques. SP produced a graded depolarizing response in LP neurons along the rostro-caudal extent of the lateral subdivision of LP nuclei (LPl), with a significantly larger response in rostral LPl neurons compared with caudal LPl neurons. In rostral LPl, SP (5,2000 nm) depolarized nearly all relay neurons tested (> 98%) in a concentration-dependent manner. Voltage-clamp experiments revealed that SP produced an inward current associated with a decreased conductance. The inward current was mediated primarily by neurokinin receptor (NK)1 tachykinin receptors, although significantly smaller inward currents were produced by specific NK2 and NK3 receptor agonists. The selective NK1 receptor antagonist RP67580 attenuated the SP-mediated response by 71.5% and was significantly larger than the attenuation of the SP response obtained by NK2 and NK3 receptor antagonists, GR159897 and SB222200, respectively. The SP-mediated response showed voltage characteristics consistent with a K+ conductance, and was attenuated by Cs+, a K+ channel blocker. Our data suggest that SP may modulate visual information that is being processed and integrated in the LPl with inputs from collicular sources. [source]

Plateau potential-dependent windup of the response to primary afferent stimuli in rat dorsal horn neurons

Valérie Morisset
Abstract In the spinal cord, repetitive stimulation of nociceptive afferent fibres induces a progressive build-up of dorsal horn neuron (DHN) responses. This ,action potential windup' is used as a cellular model of central sensitization to pain. It partly relies on synaptic plasticity, being reduced after blocking NMDA and neurokinin receptors. Using intracellular recordings in a slice preparation of the rat spinal cord, we have analysed the implication of an additional non-synaptic component of windup. Primary afferent fibres were electrically stimulated in the dorsal root. Of 47 responding deep DHNs, 17 (36%) produced action potential windup and afterdischarge during consecutive periods of repeated stimuli (0.4,1 Hz) activating high- (n = 13 neurons) and low-threshold (n = 6 neurons) afferent fibres. When the NMDA receptors were blocked, the rate of windup did not change. In all neurons, there was an absolute correlation between expression of windup and the production of calcium-dependent plateau potentials. Sensitization of the DHN response, similar to the synaptically induced windup, was obtained by repetitive intracellular injection of depolarizing current pulses. This intracellularly induced windup had the same pharmacology as the plateau potential. Synaptically induced windup was also abolished by nifedipine, an L-type calcium-channel blocker. Expression of plateau properties in DHNs is therefore a critical component of windup, operating downstream of synaptic processes. Being associated with calcium influx, generation of plateau potentials could be a link between short-term plasticity and the long-term modification of DHN excitability associated with central sensitization. [source]

Trafficking of neurokinin receptors: regulation, mechanism and function

N. Bunnett
Cellular responses to agonists of G-protein-coupled receptors (GPCRs) depend in large part on the trafficking of receptors between the plasma membrane and intracellular locations. Receptor activation usually triggers rapid endocytosis of receptors, which either recycle to the cell surface or are targeted for degradation, depending on the receptor in question and the nature of the stimulation. Activation of neurokinin receptors (NKRs) induces membrane translocation of G-protein receptor kinases, which phosphorylate the receptors and ,-arrestins, which interact with phosphorylated receptors. ,-arrestins: 1) uncouple receptors from G-proteins to mediate desensitization; 2) are adaptors for clathrin and AP-2 and mediate clathrin and dynamin-dependent endocytosis of receptors; and 3) interact with components of the MAP kinase pathway such as src, and thereby determine the subcellular location and function of activated MAP kinases. The fate of endocytosed NKRs depends on the receptor and the nature of the stimulus. Transient stimulation with low concentrations of SP (1 nm, 10 min) induces rapid recycling of the NK1R from superficially located endosomes by a mechanism that is mediated by rab4a and rab11a. Higher concentrations of SP (10 nm) induce rab5a-dependent trafficking of the NK1R to perinuclear sorting endosomes and a gradual recycling to the plasma membrane. Continuous stimulation with high concentrations of SP (100 nm, 180 min) induces NK1R ubiquitination and trafficking for degradation. The fate of endocytosed receptors also depends on their interaction with ,-arrestins. The NK1R forms stable high-affinity interactions with both ,-arrestins 1 and 2 at the plasma membrane and in endosomes, whereas the NK3R interacts transiently only with ,-arrestin 2 at the cell surface. The nature of these interactions is specified by domains in the intracellular loop 3 and the carboxyl terminus and determine the rate of recycling and resensitization of these receptors. [source]

Substance P initiates NFAT-dependent gene expression in spinal neurons

V. S. Seybold
Abstract Persistent hyperalgesia is associated with increased expression of proteins that contribute to enhanced excitability of spinal neurons, however, little is known about how expression of these proteins is regulated. We tested the hypothesis that Substance P stimulation of neurokinin receptors on spinal neurons activates the transcription factor nuclear factor of activated T cells isoform 4 (NFATc4). The occurrence of NFATc4 in spinal cord was demonstrated with RT-PCR and immunocytochemistry. Substance P activated NFAT-dependent gene transcription in primary cultures of neonatal rat spinal cord transiently transfected with a luciferase DNA reporter construct. The effect of Substance P was mediated by neuronal neurokinin-1 receptors that coupled to activation of protein kinase C, l -type voltage-dependent calcium channels, and calcineurin. Interestingly, Substance P had no effect on cyclic AMP response element (CRE)-dependent gene expression. Conversely, calcitonin gene-related peptide, which activated CRE-dependent gene expression, did not activate NFAT signaling. These data provide evidence that peptides released from primary afferent neurons regulate discrete patterns of gene expression in spinal neurons. Because the release of Substance P and calcitonin gene-related peptide from primary afferent neurons is increased following peripheral injury, these peptides may differentially regulate the expression of proteins that underlie persistent hyperalgesia. [source]

Intestinal anti-nociceptive behaviour of NK3 receptor antagonism in conscious rats: evidence to support a peripheral mechanism of action

J. Fioramonti
Abstract The involvement of neurokinin receptors in visceral nociception is well documented. However, the role and localization of NK3 receptors is not clearly established. This study was designed to determine whether NK3 receptor antagonists crossing (talnetant) or not (SB-235375) the blood,brain barrier reduce the nociceptive response to colo-rectal distension (CRD) and whether NK3 antagonism reduces inflammation- or stress-induced hypersensitivity to rectal distension. Isobaric CRD and isovolumic rectal distensions were performed in rats equipped with intramuscular electrodes to record abdominal muscle contractions. In controls, CRD induced a pressure-related (15,60 mmHg) increase in the number of abdominal contractions. Both talnetant and SB-235375 [50 mg kg,1, per oral (p.o.)], which had no effect on colo-rectal tone, reduced the number of contractions associated with CRDs from 30 to 60 mmHg. Three days after rectal instillation of TNBS, abdominal contractions were increased for rectal distension volume of 0.4 mL. This effect was not modified by talnetant (30 mg kg,1, p.o.). Partial restraint stress increased abdominal contractions at all distension volumes (0,1.2 mL). Talnetant (10 mg kg,1, p.o.) abolished the increase observed for 0.8 and 1.2 mL. These results indicate that peripheral NK3 receptor antagonism reduced nociception associated with CRD and hypersensitivity induced by stress but not inflammation. [source]