Activation of melanocortin receptors in the intermediolateral cell column of the upper thoracic cord elicits tachycardia in the rat

Abstract

Melanocortin receptors (MCRs) are present in the intermediolateral cell column of the spinal cord (IML). We tested the hypothesis that activation of MCRs in the IML elicits cardioacceleratory responses and the source of melanocortins in the IML may be the melanocortin-containing neurons in the hypothalamic arcuate nucleus (ARCN). Experiments were done in urethane-anesthetized, artificially ventilated adult male Wistar rats. Microinjections (50 nl) of α-melanocyte stimulating hormone (α-MSH) (0.4-2 mM) and adrenocorticotropic hormone (ACTH) (0.5-2 mM) into the right IML elicited increases in heart rate (HR). These tachycardic responses were blocked by microinjections of melanocortin receptor 4 (MC4R) antagonists [SHU9119 (0.25 mM) or agouti-related protein (AGRP, 0.1 mM)] into the right IML. Stimulation of right ARCN by microinjections (30 nl) of N-methyl-d-aspartic acid (NMDA, 10 mM) elicited increases in HR. Blockade of MC4Rs in the ipsilateral IML at T1-T3 using SHU9119 (0.25 mM) attenuated the tachycardic responses elicited by subsequent microinjections of NMDA into the ipsilateral ARCN. ARCN neurons retrogradely labeled by microinjections of Fluoro-Gold into the right IML showed immunoreactivity for proopiomelanocortin (POMC), α-MSH, and ACTH. Fibers immunoreactive for POMC, α-MSH, and ACTH were present in the IML at T1-T3. These results indicated that activation of MC4Rs in the right IML elicited tachycardia and one of the sources of melanocortins in the IML is the ARCN. Melanocortin levels are elevated in stress and ARCN neurons are activated during stress. Our results allude to the possibility that cardiac effects of stress may be mediated via melanocortin containing ARCN neurons that project to the IML.

Chronic Central Nervous System MC3/4R Blockade Attenuates Hypertension Induced by Nitric Oxide Synthase Inhibition but Not by Angiotensin II Infusion

“…Although the brain areas where MC3/4R exert their effects on the autonomic nervous system and BP regulation are still poorly understood, MC4R are abundant in the paraventricular nucleus of the hypothalamus (PVN) and in brainstem areas involved in autonomic regulation as well as in the intermediolateral medulla (IML) 32,33 . For example, acute stimulation of MC4R in the PVN or IML raises renal SNA and HR, respectively, 32,33 while MC4R located on cholinergic preganglionic parasympathetic and sympathetic neurons appear to contribute, at least in part, to obesity hypertension 34 . However, additional studies are needed to determine the brain regions where the melanocortin system is most important for modulating cardiovascular function.…”

The melanocortin pathway and control of appetite-progress and therapeutic implications

“…MC4R agonists increase blood pressure by targeting cholinergic neurons, including the sympathetic preganglionic neurons of the IML (Sohn et al 2013). In the IML, MC4R neurons also control heart rate (Iwasa et al 2013) (Fig. 4).…”

The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances

“…On the other hand, an α-MSH-expressing viral vector injected into the NTS increased sympathetic activity and the heart rate and reduced parasympathetic activity in mice [170]. Similarly, Iwasa et al [171] observed an increased heart rate after α-MSH had been microinjected into the IML, the location of cholinergic sympathetic preganglionic neurons. Recent work shows that re-expressing MC4Rs specifically in cholinergic neurons renders MC4R null mice hypertensive without affecting their obesity [32].…”