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 alpha-melanocyte stimulating hormone (alpha-MSH), were unilaterally microinjected into the DMV of rats, and their effects were noted on gastric activity. MT-II decreased phasic contractions, whereas alpha-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 alpha-MSH) into the overlying nucleus of the solitary tract (NTS), an important component of vago-vagal gastric circuitry, decreased phasic contractions. In addition, alpha-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 alpha-MSH significantly reduced spontaneous action potentials (but not in MC4-R-/- mice). However, in low-calcium ACSF, MT-II decreased neuronal firing, whereas alpha-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 alpha-MSH, modulates gastric activity, which may have physiological relevance for food intake and gastric function.