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2 Adrenergic receptor-mediated inhibition of thermogenesis

Madden, CJ;Tupone, D;Cano, G;Morrison, SF;

2 adrenergic receptor (2-AR) agonists have been used as antihypertensive agents, in the management of drug withdrawal, and as sedative analgesics. Since 2-AR agonists also influence the regulation of body temperature, we explored their potential as antipyretic agents. This study delineates the central neural substrate for the inhibition of rat brown adipose tissue (BAT) and shivering thermogenesis by 2-AR agonists. Nanoinjection of the 2-AR agonist clonidine (1.2 nmol) into the rostral raphe pallidus area (rRPa) inhibited BAT sympathetic nerve activity (SNA) and BAT thermogenesis. Subsequent nanoinjection of the 2-AR antagonist idazoxan (6 nmol) into the rRPa reversed the clonidine-evoked inhibition of BAT SNA and BAT thermogenesis. Systemic administration of the 2-AR agonists dexmedetomidine (25 g/kg, i.v.) and clonidine (100 g/kg, i.v.) inhibited shivering EMGs, BAT SNA, and BAT thermogenesis, effects that were reversed by nanoinjection of idazoxan (6 nmol) into the rRPa. Dexmedetomidine (100 g/kg, i.p.) prevented and reversed lipopolysaccharide-evoked (10 g/kg, i.p.) thermogenesis in free-behaving rats. Cholera toxin subunit b retrograde tracing from rRPa and pseudorabies virus transynaptic retrograde tracing from BAT combined with immunohistochemistry for catecholaminergic biosynthetic enzymes revealed the ventrolateral medulla as the source of catecholaminergic input to the rRPa and demonstrated that these catecholaminergic neurons are synaptically connected to BAT. Photostimulation of ventrolateral medulla neurons expressing the PRSx8-ChR2-mCherry lentiviral vector inhibited BAT SNA via activation of 2-ARs in the rRPa. These results indicate a potent inhibition of BAT and shivering thermogenesis by 2-AR activation in the rRPa, and suggest a therapeutic potential of 2-AR agonists for reducing potentially lethal elevations in body temperature during excessive fever.