Differential modulation of neurons in the rostral ventromedial medulla by neurokinin-1 receptors
ABSTRACT The rostral ventromedial medulla (RVM) is part of descending circuitry that modulates nociceptive processing at the level of the spinal cord. RVM output can facilitate pain transmission under certain conditions such as inflammation, and thereby contribute to hyperalgesia. Evidence suggests that substance P and activation of neurokinin-1 (NK-1) receptors in the RVM are involved in descending facilitation of nociception. We showed previously that injection of NK-1 receptor antagonists into the RVM attenuated mechanical and heat hyperalgesia produced by intraplantar injection of capsaicin. Furthermore, intraplantar injection of capsaicin excited ON cells in the RVM and inhibited ongoing activity of OFF cells. In the present studies, we therefore examined changes in responses of RVM neurons to mechanical and heat stimuli after intraplantar injection of capsaicin and determined the role of NK-1 receptors by injecting a NK-1 receptor antagonist into the RVM prior to capsaicin. After capsaicin injection, excitatory responses of ON cells and inhibitory responses of OFF cells evoked by mechanical and heat stimuli applied to the injected, but not contralateral, paw were increased. Injection of the NK-1 antagonist L-733,060 did not alter evoked responses of ON or OFF cells but attenuated the capsaicin-evoked enhanced responses of ON cells to mechanical and heat stimuli with less of an effect on the enhanced inhibitory responses of OFF cells. These data support the notion that descending facilitation from RVM contributes to hyperalgesia and that NK-1 receptors, presumably located on ON cells, play an important role in initiating descending facilitation of nociceptive transmission.
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ABSTRACT: This study examined possible mechanisms by which Substance P (Sub P) assumes a pronociceptive role in the rostral ventromedial medulla (RVM) under conditions of peripheral inflammatory injury, in this case produced by intraplantar (ipl) injection of complete Freund's adjuvant (CFA). In saline and CFA-treated rats, neurokinin-1 receptor (NK1R) immunoreactivity was localized to neurons in the RVM. Four days after ipl injection of CFA, the number of NK1R immunoreactive neurons in the RVM was increased by 30%, and there was a concomitant increase in NK1R immunoreactive processes in CFA-treated rats. Although NK1R immunoreactivity was increased, tachykinin-1 receptor (Tacr1) mRNA was not increased in the RVM of CFA-treated rats. To assess changes in Sub P release, the number of RVM neurons that exhibited NK1R internalization was examined in saline- and CFA-treated rats following noxious heat stimulation of the hind paws. Only CFA-treated rats that experienced noxious heat stimulation exhibited a significant increase in the number of neurons showing NK1R internalization. These data suggest that tonic Sub P release is not increased as a simple consequence of peripheral inflammation, but that phasic or evoked release of Sub P in the RVM is increased in response to noxious peripheral stimulation in a persistent inflammatory state. These data support the proposal that an upregulation of the NK1R in the RVM, as well as enhanced release of Sub P following noxious stimulation underlie the pronociceptive role of Sub P under conditions of persistent inflammatory injury. J. Comp. Neurol., 2014. © 2014 Wiley Periodicals, Inc.The Journal of Comparative Neurology 09/2014; 522(13). DOI:10.1002/cne.23564 · 3.51 Impact Factor
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ABSTRACT: Intraplantar injection of 0.4% formalin into the rat hind paw leads to a biphasic nociceptive response; an "acute" phase (0-15 min) and "tonic" phase (16-120 min), which is accompanied by significant phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in the contralateral striatum at 120 min post-formalin injection. To uncover a possible relationship between the slow-onset substance P (SP) release and increased ERK1/2 phosphorylation in the striatum, continuous infusion of SP into the striatum by reverse microdialysis (0.4 μg/mL in microdialysis fiber, 1 μL/min) was performed to mimic volume neurotransmission of SP. Continuous infusion for 3 hr of SP reduced the duration of "tonic" phase nociception, and this SP effect was mediated by NK1 receptors since pretreatment with the NK1R antagonist CP96345 (10 μM) blocked the effect of SP infusion. However, formalin induced "tonic" phase nociception was significantly prolonged following acute injection of the MEK1/2 inhibitor PD0325901 (100 pmol) by microinjection. The co-infusion of SP and PD0325901 significantly increased the "tonic" phase of nociception. These data demonstrate that volume transmission of striatal SP triggered by peripheral nociceptive stimulation does not lead to pain facilitation but a significant decrease of tonic nociception by the activation of the SP-NK1R-ERK1/2 system. This article is protected by copyright. All rights reserved.Journal of Neurochemistry 08/2014; 131(6). DOI:10.1111/jnc.12938 · 4.24 Impact Factor
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ABSTRACT: The effects of a mild freeze injury to the skin on responses of nociceptive dorsal horn neurons to cold and heat stimuli were examined in anesthetized rats. Electrophysiological recordings were obtained from 72 nociceptive spinal neurons located in the superficial and deep dorsal horn. All neurons had receptive fields (RFs) on the glabrous skin of the hindpaw, and neurons were functionally divided into wide dynamic range (WDR) and high-threshold (HT) neurons. Forty-four neurons (61%) were classified as WDR and responded to both innocuous and noxious mechanical stimuli (mean mechanical threshold of 12.8 +/- 1.6 mN). Twenty-eight neurons (39%) were classified as HT and were excited only by noxious mechanical stimuli (mean mechanical threshold of 154.2 +/- 18.3 mN). Neurons were characterized for their sensitivity heat (35 to 51 degrees C) and cold (28 to -12 degrees C) stimuli applied to their RF. Among WDR neurons, 86% were excited by both noxious heat and cold stimuli, while 14% responded only to heat. For HT neurons, 61% responded to heat and cold stimuli, 32% responded only to noxious heat, and 7% responded only to noxious cold. Effects of a mild freeze injury (-15 degrees C applied to the RF for 20 s) on responses to heat and cold stimuli were examined in 30 WDR and 22 HT neurons. Skin freezing was verified as an abrupt increase in skin temperature at the site of injury due to the exothermic reaction associated with crystallization. Freezing produced a decrease in response thresholds to heat and cold stimuli in most WDR and HT neurons. WDR and HT neurons exhibited a mean decrease in response threshold for cold of 9.0 +/- 1.3 degrees C and 10.0 +/- 1.6 degrees C, respectively. Mean response thresholds for heat decreased 4.0 +/- 0.4 degrees C and 4.3 +/- 1.3 degrees C in WDR and HT neurons, respectively. In addition, responses to suprathreshold cold and heat stimuli increased. WDR and HT neurons exhibited an 89% and a 192% increase in response across all cold stimuli, and a 93 and 92% increase in responses evoked across all heat stimuli, respectively. Our results demonstrate that many spinal neurons encode intensity of noxious cold as well as noxious heat over a broad range of stimulus temperatures. Enhanced responses of WDR and HT neurons to cold and heat stimuli after a mild freeze injury is likely to contribute to thermal hyperalgesia following a similar freeze injury in humans.Journal of Neurophysiology 09/2001; 86(2):986-96. · 3.04 Impact Factor