Delta Opioid Receptors and Enkephalinergic Signaling within Locus Coeruleus Promote Stress Resilience

Abstract

The noradrenergic nucleus locus coeruleus is a key component of the stress circuitry of the brain. During stress, the neuropeptide corticotropin-releasing factor (CRF) is secreted onto LC, increasing LC output and norepinephrine concentration in the brain, which is thought to promote anxiety-like behavior. LC is also innervated by several structures that synthesize and release the endogenous opioid peptide enkephalin onto LC upon stressor termination. While the role of CRF neurotransmission within LC in mediating anxiety-like behavior and the behavioral response to stress has been well characterized, the role of enkephalinergic signaling at LC-expressed δ-opioid receptors has been comparatively understudied. We have previously shown that acute stressor exposure increases LC activity and anxiety-like behavior for at least one week. Here, we extend these findings by showing that these effects may be mediated at least in part through stress-induced downregulation of DORs within LC. Furthermore, overexpression of DORs in LC blocks the effects of stress on both LC firing properties and anxiety-like behavior. In addition, intra-LC infusions of enkephalin blocked stress-induced freezing behavior and promoted conditioned place preference. These findings indicate that enkephalinergic neurotransmission at DORs within LC is an important component of the behavioral response to stress and may drive reward-related behavior as well.

Endogenous opioids gate the locus coeruleus pain generator

“…Previous studies have shown lesions or blockade of LC activity reverses neuropathic injury-induced hypersensitivity( 8, 9 ). Therefore, it stands to reason that other endogenous inhibitory systems within the LC may produce similar behavioral responses( 25, 59–63, 82, 86, 90 – 97 ). Future work should pursue this hypothesis to identify new, potentially analgesic mechanisms.…”

Teneurin C-terminal associated peptide (TCAP)-1 attenuates the development and expression of naloxone-precipitated morphine withdrawal in male Swiss Webster mice

“…These studies establish that TCAP-1 inhibits both CRF stress and addiction-related behaviors, but these attenuating effects on behavior associated with cocaine -a psychostimulant -may not necessarily generalize to other classes of psychoactive drugs, such as opioids. However, because the opioid-associated neurological circuit encompasses both stress-and addiction-related behaviors (Crowley and Kash 2015; Haun et al 2022;Leconte et al 2022;Rysztak and Jutkiewicz 2022;Simmons et al 2020;Tkaczynski et al 2022;Zhang et al 2022), and because opioid cessation results in withdrawal which is itself as stressor, it is possible that TCAP-1 could have utility in facilitating opioid abstinence.…”