The locus coeruleus maintains core body temperature and protects against hypothermia during dexmedetomidine-induced sedation.

Abstract

Activating the <i>adra2a</i> receptors of the brain's norepinephrine (NE) system produces NREM-like sleep and hypothermia. Dexmedetomidine (DEX), a selective α2 receptor (<i>adra2a</i>) agonist, is an important drug used in intensive care for arousable sedation. But for some patients, even slight decreases in body temperature during sedation could pose health risks such as increasing the likelihood of postoperative cognitive dysfunction. Where are the <i>adra2a</i> receptors at which DEX acts to induce hypothermia? A popular theory is that inhibitory <i>adra2a</i> receptors expressed on norepinephrinergic locus coeruleus (LC) neurons are DEX's prime targets. To examine this, we genetically lesioned <i>galanin</i> (<i>gal</i>)-expressing norepinephrinergic LC neurons in adult mice. In these <i>ΔLC</i> mice, baseline sleep-wake levels were unchanged, but surprisingly, core body temperatures were lower. Maintaining body temperature depended on NE/<i>gal</i> projections from the LC to the medial preoptic (MPO) hypothalamus. Furthermore, without these LC neurons, DEX induced hypothermia more strongly. Knockdown with <i>adra2a shRNA</i> revealed that DEX induces hypothermia via <i>adra2a</i> receptors on MPO glutamate cells. When <i>ΔLC</i> mice were kept warm, DEX could induce the same amount of NREM-like sleep as well as it did for mice with an intact LC, and this sleep-like state in <i>ΔLC</i> mice had a higher delta frequency power than in control mice. Our results emphasize that inhibition of the LC by DEX is not required to induce robust sedation. By contrast, the LC likely has a fortuitous background action in protecting against drug-induced hypothermia and speeds recovery from hypothermia.