Melanocortin-4 receptor expression in the rostral ventromedial medulla involved in modulation of nociception in transgenic mice

Abstract

The rostral ventromedial medulla (RVM) is a prominent component of the descending modulatory system involved in the control of spinal nociceptive transmission. In the current study, we investigated melanocortin-4 receptor (MC4R) expression in the RVM, where the neurons involved in modulation of nociception reside. Using a line of mice expressing green fluorescent protein (GFP) under the control of the MC4R promoter, we found a large number of GFP-positive neurons in the RVM [nucleus raphe magnus (NRM) and nucleus gigantocellularis pars α (NGCα)]. Fluorescence immunohistochemistry revealed that approximately 10% of MC4R-GFP-positive neurons coexpressed tyrosine hydroxylase, indicating that they were catecholaminergic, whereas 50%–75% of those coexpressed tryptophan hydroxylase, indicating that they were serotonergic. Our findings support the hypothesis that MC4R signaling in RVM may modulate the activity of serotonergic sympathetic outflow sensitive to nociceptive signals, and that MC4R signaling in RVM may contribute to the descending modulation of nociceptive transmission.

Keywords

melanocortin-4 receptor / nociception / rostral ventromedial medulla

References

[1] LeongML, GuM, Speltz-PaizR, et al.. Neuronal loss in the rostral ventromedial medulla in a rat model of neuropathic pain. J Neurosci, 2011, 31(47): 17 028-17 039

[2] WeiF, DubnerR, ZouS, et al.. Molecular depletion of descending serotonin unmasks its novel facilitatory role in the development of persistent pain. J Neurosci, 2010, 30(25): 8624-8636

[3] TaoYX. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev, 2010, 31(4): 506-543

[4] ChuH, SunJ, XuH, et al.. Effect of periaqueductal gray melanocortin 4 receptor in pain facilitation and glial activation in rat model of chronic constriction injury. Neurol Res, 2012, 34(9): 871-888

[5] LiuH, KishiT, RoseberryAG, et al.. Transgenic mice expressing green fluorescent protein under the control of the melanocortin-4 receptor promoter. J Neurosci, 2003, 23(18): 7143-7154

[6] SaykF, HeutlingD, DodtC, et al.. Sympathetic function in human carriers of melanocortin-4 receptor gene mutations. J Clin Endocrinol Metab, 2010, 95(4): 1998-2002

[7] GreenfieldJR, MillerJW, KeoghJM, et al.. Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med, 2009, 360(1): 44-52

[8] GreenfieldJR. Melanocortin signalling and the regulation of blood pressure in human obesity. J Neuroendocrinol, 2011, 23(2): 186-193

[9] LeeTK, LoisJH, TroupeJH, et al.. Transneuronal tracing of neural pathways that regulate hindlimb muscle blood flow. Am J Physiol Regul Integr Comp Physiol, 2007, 292(4): R1532-R1541

[10] RossiJ, BalthasarN, OlsonD, et al.. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab, 2011, 13(2): 195-204

[11] YeD, GuoQ, FengJ, et al.. Laterodorsal tegmentum and pedunculopontine tegmental nucleus circuits regulate renal functions: Neuroanatomical evidence in mice models. J Huazhong Univ Sci Technol Med Sci, 2012, 32(2): 216-220

[12] YeDW, LiRC, WuW, et al.. Role of spinal cord in regulating mouse kidney: A virally mediated trans-synaptic tracing study. Urology, 2012, 79(3): 745.e1-745.e4

[13] BarkerJR, ThomasCF, BehanM. Serotonergic projections from the caudal raphe nuclei to the hypoglossal nucleus in male and female rats. Respir Physiol Neurobiol, 2009, 165(2–3): 175-184

[14] Voss-AndreaeA, MurphyJG, EllacottKL, et al.. Role of the central melanocortin circuitry in adaptive thermogenesis of brown adipose tissue. Endocrinology, 2007, 148(4): 1550-1560

[15] FranklinKB, PaxinosG. . The Mouse Brain in Stereotaxic Coordinates, 2007Third EditionSan Diego, CA, Academic Press

[16] KermanIA, EnquistLW, WatsonSJ, et al.. Brainstem substrates of sympatho-motor circuitry identified using trans-synaptic tracing with pseudorabies virus recombinants. J Neurosci, 2003, 23(11): 4657-4666

[17] BrazJM, EnquistLW, BasbaumAI. Inputs to serotonergic neurons revealed by conditional viral transneuronal tracing. J Comp Neurol, 2009, 514(2): 145-160

[18] XiangHB, LiuC, GuoQQ, et al.. Deep brain stimulation of the pedunculopontine tegmental nucleus may influence renal function. Med Hypotheses, 2011, 77(6): 1135-1138

[19] ElmquistJK. Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin. Int J Obes Relat Metab Disord, 2001, 25(Suppl5): S78-S82

[20] ElmquistJK. Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin. Physiol Behav, 2001, 74(4–5): 703-708

[21] SaperCB, ChouTC, ElmquistJK. The need to feed: homeostatic and hedonic control of eating. Neuron, 2002, 36(2): 199-211

[22] HeislerLK, CowleyMA, KishiT, et al.. Central serotonin and melanocortin pathways regulating energy homeostasis. Ann N Y Acad Sci, 2003, 994: 169-174

[23] LuN, HanM, YangZL, et al.. Nociceptin/Orphanin FQ in PAG modulates the release of amino acids, serotonin and norepinephrine in the rostral ventromedial medulla and spinal cord in rats. Pain, 2010, 148(3): 414-425

[24] HayashidaK, KimuraM, YoshizumiM, et al.. Ondansetron reverses antihypersensitivity from clonidine in rats after peripheral nerve injury: role of gamma-amin-obu-tyric acid in alpha2-adrenoceptor and 5-HT3 serotonin receptor analgesia. Anesthesiology, 2012, 117(2): 389-398