Differential modulation of neurons in the rostral ventromedial medulla by neurokin-1 receptors

Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis 55455, USA.
Journal of Neurophysiology (Impact Factor: 2.89). 02/2012; 107(4):1210-21. DOI: 10.1152/jn.00678.2011
Source: PubMed


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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Available from: Al J Beitz, Dec 07, 2015
    • "Three different cell types have been identified in the RVM of anaesthetized animals and named after their phasic response to an acute noxious stimulus: ON cells exhibit a burst in firing; OFF cells exhibit a pause in firing; and neutral cells show no consistent response (Fields et al., 1983; Barbaro et al., 1986; Heinricher et al., 2009). Theories of RVM function have shifted from a focus on tonic firing of cells (Heinricher et al., 1989) to their phasic response to noxious stimuli (Heinricher & Kaplan, 1991; Mason, 2012) and the RVM is increasingly implicated in central sensitization observed in chronic pain states (Carlson et al., 2007; Brink et al., 2012; Khasabov et al., 2012). The balance of ON and OFF cell activity is likely to play a key role in the maintenance of hyperalgesia and allodynia in such states (Leong et al., 2011; Cleary et al., 2014), and recent evidence suggests that even neutral cells may play a previously under-appreciated role by adopting ON-like or OFF-like functionality (Khasabov et al., 2015). "
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    ABSTRACT: The rostral ventromedial medulla (RVM) regulates a range of involuntary behaviours but is most often associated with nociception via the action of pro-nociceptive ON cells and anti-nociceptive OFF cells. Phasic responses of ON and OFF cells determine whether or not incoming noxious signals provoke a withdrawal reflex and previous studies have suggested that reflex RVM activity patterns actively shape motor output. Here we challenge the model by using juvenile rats which are known to exhibit markedly different reflex responses compared to adults. By recording single-cell activity in the RVM and electromyographic responses of hind-limb flexor muscles to noxious thermal stimulation we found the juvenile reflex had a shorter onset latency, was larger in amplitude and exhibited a decreased rise time compared to the adult reflex. Responses of ON and OFF cells faithfully tracked the shorter onset latency of the reflex by also responding earlier and, thus, still preceded the reflex. However, neither the reflex amplitude nor the ongoing response profile was predicted by the firing rate of RVM cells in either age group. Instead we found a close correspondence between RVM activity and the reflex only during the initiation of the response. Furthermore, the short rise time of the juvenile reflex was reflected in higher rates of change of both ON and OFF cell firing. Our data suggest that the RVM is associated only with the initiation of reflexes and does not shape ongoing muscle activity which is more likely to be subserved by downstream spinal processes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · May 2015 · European Journal of Neuroscience
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    • "Iontophoretic application of Sub P excites ON cells, a population of putative pain facilitatory neurons in the RVM (Budai et al., 2007). Moreover, the enhanced ON cell activity observed in rats that received ipl injection of capsaicin can be blocked by iontophoresis of a NK1R antagonist in the RVM (Budai et al., 2007; Brink et al., 2012). However, several other mechanisms may contribute to the pronociceptive role of Sub P. One possibility is an upregulation in the number or affinity of NK1R in the RVM. "
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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.
    Full-text · Article · Sep 2014 · The Journal of Comparative Neurology
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    • "Lesioning of the RVM or injection of local anesthetic into the RVM blocks the development of injury-induced cutaneous hypersensitivity. Moreover, disabling the RVM 'facilitatory pathway,' after microinjection with either short hairpin RNA (shRNA) to block expression of tryptophan hydroxylase-2, the rate-limiting enzyme in the synthesis of neuronal serotonin, or lidocaine, attenuate the tonic, but not the early or phasic, phase of formalin-induced nociception, and capsaicin-evoked mechanical hypersensitivity (Pacharinsak et al. 2008; Wei et al. 2010; Brink et al. 2012). The RVM contains physiologically defined neurons which both inhibit and facilitate nociceptive processing at the level of the spinal dorsal horn (Urban and Gebhart 1999). "
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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.
    Full-text · Article · Aug 2014 · Journal of Neurochemistry
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