Melanocortin signaling in the brainstem influences vagal outflow to the stomach.
Activation of melanocortin 4 receptors (MC4-Rs) in brain nuclei associated with food intake profoundly influences consummatory behavior. Of these nuclei, the dorsal motor vagal nucleus (DMV), which has a dense concentration of MC4-Rs, is an important regulator of gastric tone and motility. Hence, the present study sought to examine the role of MC4-Rs in this nucleus on these activities. Using an in vivo approach, MC4-R agonists, melanotan-II (MT-II) or α-melanocyte stimulating hormone (α-MSH), were unilaterally microinjected into the DMV of rats, and their effects were noted on gastric activity. MT-II decreased phasic contractions, whereas α-MSH increased their amplitude. Both effects were blocked by the MC4-R antagonist SHU9119 or by ipsilateral vagotomy. Microinjection of the agonists (MT-II and α-MSH) into the overlying nucleus of the solitary tract (NTS), an important component of "vago-vagal" gastric circuitry, decreased phasic contractions. In addition, α-MSH reduced gastric tone and mean arterial blood pressure. To study the underlying mechanisms of the effect of MC4-R stimulation on gastric activity, electrophysiological recordings were made from labeled DMV antrum neurons in rat pups and MC4-R(-/-) mice. Bath application of MT-II or α-MSH significantly reduced spontaneous action potentials (but not in MC4-R(-/-) mice). However, in low-calcium ACSF, MT-II decreased neuronal firing, whereas α-MSH increased it. These effects mirror those of our in vivo DMV studies. Altogether, our novel findings show that activation of MC4-Rs in the brainstem, particularly in the medial NTS by the endogenous peptide α-MSH, modulates gastric activity, which may have physiological relevance for food intake and gastric function.
Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20057, USA.
Janell
J
Richardson
Maureen T
MT
Cruz
Usnish
U
Majumdar
Amanda
A
Lewin
Kathryn A
KA
Kingsbury
Ghazaul
G
Dezfuli
Stefano
S
Vicini
Joseph G
JG
Verbalis
Kenneth L
KL
Dretchen
Richard A
RA
Gillis
Niaz
N
Sahibzada
D000818:Animals; D001933:Brain Stem / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013270:Stomach / Q000294:innervation*; D014630:Vagus Nerve / Q000502:physiology; D000521:alpha-MSH / Q000378:metabolism / Q000494:pharmacology
D044105:Receptor, Melanocortin, Type 4; D000521:alpha-MSH