Medullary Raphe Neurons Facilitate Brown Adipose Tissue Activation

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Abstract
Recent evidence suggests that neurons in the medullary raphe are critical to the activation of brown adipose tissue (BAT), the major source of nonshivering heat production in the rat. Yet it is unclear which medullary raphe cells participate in cold defense and how participating cells contribute to BAT activation. Therefore, we recorded extracellularly from raphe cells during three thermoregulatory challenges that evoked an increase in BAT temperature in anesthetized rats: central cold, ambient cold, or intracerebroventricular prostaglandin E2 (PGE2) injection. Physiologically identified serotonergic (p5HT) cell discharge increased in response to cold or PGE2 administration and was positively correlated with BAT temperature. However, none of the 147 physiologically identified non-serotonergic (non-p5HT) cells recorded responded to thermoregulatory challenges that evoked an increase in BAT temperature. To test for modulation of BAT activation by non-p5HT cells that are either excited (ON cells) or inhibited (OFF cells) by noxious cutaneous stimulation, noxious stimuli were applied during evoked BAT temperature increases. Noxious stimulation suppressed BAT activation, suggesting that cells inhibited by noxious stimulation facilitate spinal circuits controlling BAT. To test whether medullary OFF cells modulate BAT activity, the μ-opiate receptor agonist (d-Ala2, N-Me-Phe4, Gly-ol5)-enkephalin (DAMGO) was microinjected into the raphe magnus, a manipulation that selectively activates OFF cells. DAMGO microinjection blocked noxious stimulation-evoked suppression of PGE2-induced BAT temperature increases. Thus, both p5HT and non-p5HT OFF cells in the medullary raphe facilitate BAT activation in response to cold challenge or pyrogen.