Further studies on opioids and hibernation: Delta opioid receptor ligand selectively induced hibernation in summer-active ground squirrels

doi:10.1016/0024-3205(88)90406-7

Life Sciences

Volume 43, Issue 19, 1988, Pages 1565-1574

https://doi.org/10.1016/0024-3205(88)90406-7 Get rights and content

Abstract

To examine the possible involvement of multiple opioid receptors in animal hibernation, we infused opioids selective for $mu$ , $kappa$ , and $delta$ opioid receptors into summer-active ground squirrels ( $Citellus tridecemlineatus$ ). The effects of those opioid treatments on the hibernation induced by HIT (Hibernation Induction Trigger) were also examined. $Mu$ opioids morphine (1.50 mg/kg/day) and morphiceptin (0.82 mg/kg/day) and $kappa$ opioid peptide dynorphin A (0.82 mg/kg/day) did not induce hibernation. On the contrary, morphine, morphiceptin and dynorphin A antagonized HIT-induced hibernation in summer-active ground squirrels. Infusion of $delta$ opioid DADLE (D-Ala²-D-Leu⁵ enkephalin; 1.50 mg/kg/day), however, induced summer hibernation in a manner comparable to that induced by HIT. It is concluded therefore that $delta$ opioid receptor and its ligand may be intimately involved in animal hibernation. In view of the fact that HIT was obtained from winter hibernating animals and might therefore be responsible for natural hibernation, our results also suggest that naturally occuring $mu$ and $kappa$ opioids may play an important role in the arousal state of hibernation.

References (17)

P.R. Oeltgen et al.
Pharm. Biochem. and Behavior
(1982)
P.R. Oeltgen et al.
Life Sci.
(1987)
R.A. Lahti et al.
Eur. J. Pharmacol.
(1985)
K.J. Chang et al.
J. Biol. Chem.
(1979)
A.R. Dawe et al.
Cryobiology
(1972)
A.R. Dawe
Hibernation trigger research updated
M.-P. Morin-Surun et al.
Eur. J. Pharmacol.
(1984)
J.W. Holaday
Peptides
(1982)

There are more references available in the full text version of this article.

Cited by (117)

Molecular strategies used by hibernators: Potential therapeutic directions for ischemia reperfusion injury and preservation of human donor organs
2020, Transplantation Reviews
Citation Excerpt :
DOR activation is induced via [D-ala2, D-leU5]-enkephalin (DADLE). DADLE is an agonist that interacts specifically with DORs and has been associated with natural organ protection during hibernation in the brain, heart, lungs, liver, and kidneys [77–82]. DOR activation through DADLE was found to inhibit cellular apoptosis and increase autophagy in rat astrocytes, offering protection in ischemic brains (Fig. 4, table) [83].
[D-Ala <sup>2</sup> , D-Leu <sup>5</sup> ] Enkephalin Improves Liver Preservation During Normothermic Ex Vivo Perfusion
2019, Journal of Surgical Research
Meeting the metabolic demands of donor livers using normothermic ex vivo liver perfusion (NEVLP) preservation technology is challenging. The delta opioid agonist [D-Ala2, D-Leu5] enkephalin (DADLE) has been reported to decrease the metabolic demand in models of ischemia and cold preservation. We evaluated the therapeutic potential of DADLE by investigating its ability to protect against oxidative stress and hepatic injury during normothermic perfusion.
Primary rat hepatocytes were used in an in vitro model of oxidative stress to determine the minimum dose of DADLE needed to induce protection and the mechanisms associated with protection. NEVLP was then used to induce injury in rat livers and determine the effectiveness of DADLE in preventing liver injury.
In hepatocytes, DADLE was protective against oxidative stress and led to a decrease in phosphorylation of JNK and p38. Naltrindole, a δ-opioid receptor antagonist, blocked this effect. DADLE also activated the PI3K/Akt signaling pathway, and PI3K/Akt inhibition decreased the protective effects of DADLE treatment. In addition, DADLE treatment during NEVLP resulted in lower perfusate alanine aminotransferase and tissue malondialdehyde and better tissue adenosine triphosphate and glutathione. Furthermore, perfusion with DADLE compared with perfusate alone preserved tissue architecture.
DADLE confers protection against oxidative stress in hepatocytes and during NEVLP. These data suggest that the mechanism of protection involved the prevention of mitochondrial dysfunction by opioid receptor signaling and subsequent increased expression of prosurvival/antiapoptotic signaling pathways. Altogether, data suggest that opioid receptor agonism may serve as therapeutic target for improved liver protection during NEVLP.
Exploring principles of hibernation for organ preservation
2016, Transplantation Reviews
Interest in mimicking hibernating states has led investigators to explore the biological mechanisms that permit hibernating mammals to survive for months at extremely low ambient temperatures, with no food or water, and awaken from their hibernation without apparent organ injury. Hibernators have evolved mechanisms to adapt to dramatic reductions in core body temperature and metabolic rate, accompanied by prolonged periods without nutritional intake and at the same time tolerate the metabolic demands of arousal. This review discusses the inherent resilience of hibernators to kidney injury and provides a potential framework for new therapies targeting ex vivo preservation of kidneys for transplantation.
D-Ala2, D-Leu5 encephalin (DADLE) reversibly inhibits cellular transcription in neurons without causing cell injury
2014, Brain Research
Citation Excerpt :
DADLE is one of such agents (Borlongan et al., 2004). It induces hibernation when injected into squirrels in summer(Su, 2000) and prolongs survival of peripheral organs such as liver and lung preserved for transplantation (Borlongan et al., 2004; Oeltgen et al., 1988, 1996). The current study focused on neurons and found that DADLE was able to reduce their metabolism without causing cell injury.
[d-Ala(2)-d-Leu(5)]-Enkephalin (DADLE) has shown promising results in protecting neurons from damages. However, the mechanism for this protection is still under investigation. The current study was carried out to test the hypothesis that DADLE may regulate cellular transcription in neurons. SH-SY5Y cells and primary cortical neurons were treated with various doses of DADLE for 24–72 h. Results demonstrated that DADLE, at all doses and time points examined, significantly inhibited cellular transcription in both cells without causing cell injury. Following recovery for 72 h without DADLE in primary neurons, the transcriptional activity fully resumed. Delta opioid receptor (DOR) is not involved in this process, as Naltrindole could not abolish DADLE׳s transcriptional inhibitory effects. Further studies in primary cortical neurons show that DADLE significantly inhibited phosphorylation of Ser2 and Ser5 of the C-terminal domain (CTD) of RNA polymerase II. These data indicate that DADLE is able to decrease cellular transcription through inhibiting phosphorylation of RNA polymerase II in neurons, which may provide mechanistic insight into its reported neuroprotective effects, and suggests that it warrants further exploration as a potential therapeutic strategy for neuroprotection.
Anorexia nervosa: A rogue hibernation?
2014, Medical Hypotheses
Anorexia nervosa is a puzzling and often tragic disorder which causes the individual to self starve and hyper-exercise. We present a speculative analysis of the disorder which begins by acknowledging and accepting the adaptation to flee famine theory. This theory holds that anorexia nervosa results from activation of an archaic pathway that functioned well during human’s nomadic past. We advance this idea by suggesting that the faulty signal indicating there is a famine, arises from misalignment of the circadian/circannual oscillations. Entry and exit from hibernation is dependent on these cycles, and we draw an analogy between hibernation and anorexia nervosa. We offer ideas for testing the hypothesis, and targeting these faulty signals.
Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound
2023, Nature Metabolism

View all citing articles on Scopus

View full text

Further studies on opioids and hibernation: Delta opioid receptor ligand selectively induced hibernation in summer-active ground squirrels

Abstract

Pharm. Biochem. and Behavior

Life Sci.

Eur. J. Pharmacol.

J. Biol. Chem.

Cryobiology

Eur. J. Pharmacol.

Peptides