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: 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; DOI:10.1111/jnc.12938 · 4.24 Impact Factor
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ABSTRACT: The rostral ventromedial medulla (RVM) projects to the medullary and spinal dorsal horns and is a major source of descending modulation of nociceptive transmission. Traditionally, neurons in the RVM are classified functionally as ON, OFF and NEUTRAL cells based on responses to noxious cutaneous stimulation of the tail or hind paw. ON cells facilitate nociceptive transmission, OFF cells are inhibitory, whereas NEUTRAL cells are unresponsive to noxious stimuli and their role in pain modulation is unclear. Classification of RVM neurons with respect to stimulation of craniofacial tissues is not well defined. In isoflurane-anesthetized male rats, RVM neurons first were classified as ON (25.5%), OFF (25.5%) or NEUTRAL cells (49%) by noxious tail pinch. Pinching the skin overlying the temporomandibular joint (TMJ) altered the proportions of ON (39.2%) and OFF (42.2%) and NEUTRAL cells (19.6%). To assess the response of RVM cells to specialized craniofacial inputs, adenosine triphosphate (ATP; 0.01-1 mM) was injected into the TMJ (0.01-1 mM ATP) and capsaicin (0.1%) was applied to the ocular surface. TMJ and ocular surface stimulation also resulted in a reduced proportion of NEUTRAL cells compared to tail pinch. Dose-effect analyses revealed that ON and OFF cells encoded the intra-TMJ concentration of ATP. These results suggest that somatotopy plays a significant role in the functional classification of RVM cells and support the notion that NEUTRAL cells likely are sub-groups of ON and OFF cells. It is suggested that a portion of RVM neurons serves different functions in modulating craniofacial and spinal pain conditions.Journal of Neurophysiology 09/2014; 113(1). DOI:10.1152/jn.00125.2014 · 3.04 Impact Factor
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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 02/2014; 522(13). DOI:10.1002/cne.23564 · 3.51 Impact Factor