NK-1 receptors in the rostral ventromedial medulla contribute to hyperalgesia produced by intraplantar injection of capsaicin

Department of Diagnostic and Biological Science, School of Dentistry, University of Minnesota, 515 Delaware Street SE, Minneapolis, MN 55455, USA.
Pain (Impact Factor: 5.21). 05/2008; 139(1):34-46. DOI: 10.1016/j.pain.2008.02.032
Source: PubMed


The rostral ventromedial medulla (RVM) is an area of the brainstem involved in the descending modulation of nociception at the level of the spinal cord. Although the RVM is involved in the inhibition or facilitation of nociception, the underlying mechanisms are not understood. Here we examined the role of the neuropeptide substance P and neurokinin-1 (NK-1) receptors located in the RVM on withdrawal responses evoked by mechanical and heat stimuli applied to the rat hindpaw under normal conditions and during hyperalgesia produced by capsaicin. The mechanical withdrawal threshold was obtained using von Frey monofilaments applied to the plantar surface of the hindpaw. Sensitivity to heat was determined by measuring the latency to withdrawal from radiant heat applied to the plantar surface. Mechanical and heat hyperalgesia were defined as a decrease in withdrawal response threshold or latency, respectively. Rats were prepared with a chronic cannula and either vehicle or the NK-1 receptor antagonists, L-733,060 or RP-67580, was injected into the RVM. Paw withdrawal responses were obtained before and after RVM injection, and then at 5, 30, and 60 min after an intraplantar injection of capsaicin (10 microg). Injection of the NK-1 antagonists at doses of 0.5 pmol or higher did not alter withdrawal responses to mechanical or heat stimuli under normal conditions but reduced the duration of nocifensive behavior and the mechanical and heat hyperalgesia produced by capsaicin. These findings suggest that the activation of NK-1 receptors in the RVM contributes to the hyperalgesia produced by capsaicin.

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    • "The RVM contains high concentrations of Sub P, which originates from the nucleus cuneiformis and periaqueductal gray (Beitz, 1982; Chen et al., 2013), as well as moderate levels of the neurokinin-1 receptor (NK1R) (Saffroy et al., 1988; Nakaya et al., 1994). Microinjection of NK1R antagonists in the RVM (Pacharinsak et al., 2008; Hamity et al., 2010; Lagraize et al., 2010; Brink et al., 2012) can prevent or reverse mechanical hypersensitivity or heat hyperalgesia following peripheral inflammatory injury. These same antagonists are without effect in the absence of injury. "
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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 · 3.23 Impact Factor
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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.
    Journal of Neurochemistry 08/2014; 131(6). DOI:10.1111/jnc.12938 · 4.28 Impact Factor
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    • "The RVM is a midline structure that lacks laterality and projects neurons bilaterally to the ventral Vi/Vc [14]. NK1-R activation in the RVM has been shown to contribute to capsaicin-induced hyperalgesia [22]. Similarly, we showed that NK1-R activation in the RVM is involved in mediating behavioral hyperalgesia after hindpaw inflammation [24]. "
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    ABSTRACT: Background Our previous studies have shown that complete Freund’s adjuvant (CFA)-induced masseter inflammation and microinjection of the pro-inflammatory cytokine interleukin-1β (IL-1β) into the subnucleus interpolaris/subnucleus caudalis transition zone of the spinal trigeminal nucleus (Vi/Vc) can induce contralateral orofacial hyperalgesia in rat models. We have also shown that contralateral hyperalgesia is attenuated with a lesion of the rostral ventromedial medulla (RVM), a critical site of descending pain modulation. Here we investigated the involvement of the RVM-Vi/Vc circuitry in mediating contralateral orofacial hyperalgesia after an injection of CFA into the masseter muscle. Results Microinjection of the IL-1 receptor antagonist (5 nmol, n=6) into the ipsilateral Vi/Vc attenuated the CFA-induced contralateral hyperalgesia but not the ipsilateral hyperalgesia. Intra-RVM post-treatment injection of the NK1 receptor antagonists, RP67580 (0.5-11.4 nmol) and L-733,060 (0.5-11.4 nmol), attenuated CFA-induced bilateral hyperalgesia and IL-1β induced bilateral hyperalgesia. Serotonin depletion in RVM neurons prior to intra-masseter CFA injection prevented the development of contralateral hyperalgesia 1–3 days after CFA injection. Inhibition of 5-HT3 receptors in the contralateral Vi/Vc with direct microinjection of the select 5-HT3 receptor antagonist, Y-25130 (2.6-12.9 nmol), attenuated CFA-induced contralateral hyperalgesia. Lesions to the ipsilateral Vc prevented the development of ipsilateral hyperalgesia but did not prevent the development of contralateral hyperalgesia. Conclusions These results suggest that the development of CFA-induced contralateral orofacial hyperalgesia is mediated through descending facilitatory mechanisms of the RVM-Vi/Vc circuitry.
    Molecular Pain 10/2012; 8(1):78. DOI:10.1186/1744-8069-8-78 · 3.65 Impact Factor
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