Endogenous central amygdala mu-opioid receptor signaling promotes sodium appetite in mice

Abstract

Due to the importance of dietary sodium and its paucity within many inland environments, terrestrial animals have evolved an instinctive sodium appetite that is commensurate with sodium deficiency. Despite a well-established role for central opioid signaling in sodium appetite, the endogenous influence of specific opioid receptor subtypes within distinct brain regions remains to be elucidated. Using selective pharmacological antagonists of opioid receptor subtypes, we reveal that endogenous mu-opioid receptor (MOR) signaling strongly drives sodium appetite in sodium-depleted mice, whereas a role for kappa (KOR) and delta (DOR) opioid receptor signaling was not detected, at least in sodium-depleted mice. Fos immunohistochemistry revealed discrete regions of the mouse brain displaying an increased number of activated neurons during sodium gratification: the rostral portion of the nucleus of the solitary tract (rNTS), the lateral parabrachial nucleus (LPB), and the central amygdala (CeA). The CeA was subsequently targeted with bilateral infusions of the MOR antagonist naloxonazine, which significantly reduced sodium appetite in mice. The CeA is therefore identified as a key node in the circuit that contributes to sodium appetite. Moreover, endogenous opioids, acting via MOR, within the CeA promote this form of appetitive behavior.

The effect of increased NaCl intake on rat brain endogenous μ‐opioid receptor signalling

“…In addition to receiving gustatory information about salt, it is important to take into account that a bi‐directional opioid‐opioid signalling pathway exists between the rostral NTS and the CeA, which influences appetitive behaviours such as food intake via MORs . A similar opioid circuitry exists within the LPBN that projects to the CeA, which then activates the mesolimbic reward system involved in the motivation to consume salt and its rewarding palatability …”

“…Several lines of evidence suggest that central endogenous opioid peptides and receptors are involved in the regulation of salt ingestion. β‐endorphin, comprising one of these, plays a key role in the modulation of salt hedonic palatability and sodium appetite, as well as in dietary‐sodium‐overload induced sympathetic and pressor responses . Previous results from our laboratory indicated that β‐endorphin knockout mice and heterozygous mutant mice consume approximately 50% less 2% NaCl solution than wild‐type mice after sodium depletion, suggesting that β‐endorphin facilitates induced sodium appetite .…”

“…Moreover, systemic injection of morphine increased the preference of mice and rats for normally aversive hypertonic NaCl solutions (1.5%‐30% NaCl) . Increased MOR signalling along the nucleus accumbens, ventral pallidum and central amygdala nucleus (CeA) has been mainly associated with the hedonic palatability of NaCl when it is tasted . MOR activity along the brainstem, within the lateral parabrachial nucleus (LPBN) and the nucleus of the solitary tract (NTS), mainly modulates motivated sodium/food intake and blood pressure …”

“…13,14 Increased MOR signalling along the nucleus accumbens, ventral pallidum and central amygdala nucleus (CeA) has been mainly associated with the hedonic palatability of NaCl when it is tasted. 5,[15][16][17] MOR activity along the brainstem, within the lateral parabrachial nucleus (LPBN) and the nucleus of the solitary tract (NTS), mainly modulates motivated sodium/food intake and blood pressure. [18][19][20][21] However, experiments such as these fail to determine the mechanisms by which endogenous MOR signalling acts to modulate sodium appetite and blood pressure regulation.…”

The Neurocircuitry of fluid satiation

“…It is likely that NaCl intake by the CeA is mediated by endogenous opioids, given that injection of μ‐opioid receptor antagonists into the CeA significantly decreases NaCl intake appetite in mice (Smith et al. ). Studies also suggest that the PBN and CeA interact to control NaCl intake: deactivating the PBN increases NaCl intake, which is blocked by intra‐CeA injection of opioid receptor antagonists (Andrade‐Franze et al.…”