Episodic Ethanol Exposure in Adolescent Rats Causes Residual Alterations in Endogenous Opioid Peptides

Abstract

Adolescent binge drinking is associated with an increased risk of substance use disorder, but how ethanol affects the central levels of endogenous opioid peptides is still not thoroughly investigated. The aim of this study was to examine the effect of repeated episodic ethanol exposure during adolescence on the tissue levels of three different endogenous opioid peptides in rats. Outbred Wistar rats received orogastric (i.e., gavage) ethanol for three consecutive days per week between 4 and 9 weeks of age. At 2 h and 3 weeks, respectively, after the last exposure, beta-endorphin, dynorphin B and Met-enkephalin-Arg6Phe7 (MEAP) were analyzed with radioimmunoassay. Beta-endorphin levels were low in the nucleus accumbens during ethanol intoxication. Remaining effects of adolescent ethanol exposure were found especially for MEAP, with low levels in the amygdala, and high in the substantia nigra and ventral tegmental area three weeks after the last exposure. In the hypothalamus and pituitary, the effects of ethanol on beta-endorphin were dependent on time from the last exposure. An interaction effect was also found in the accumbal levels of MEAP and nigral dynorphin B. These results demonstrate that repeated episodic exposure to ethanol during adolescence affected opioid peptide levels in regions involved in reward and reinforcement as well as stress response. These alterations in opioid networks after adolescent ethanol exposure could explain, in part, the increased risk for high ethanol consumption later in life.

Acupuncture attenuates alcohol dependence through activation of endorphinergic input to the nucleus accumbens from the arcuate nucleus

“…These findings raise the possibility that the diminished -endorphin release in the NAc may be attributed to suppression of endorphinergic input to the NAc during withdrawal from chronic ethanol. Similarly, it has been shown that NAc -endorphin levels in the ethanolintoxicated state were significantly decreased compared with waterintoxicated state (30). As hypothalamic endorphinergic neurons innervate the NAc (10), the decreased -endorphinergic neuron activity during ethanol withdrawal would result in the excitation of NAc GABA neurons in the NAc.…”

Moderate adolescent chronic intermittent ethanol exposure sex-dependently disrupts synaptic transmission and kappa opioid receptor function in the basolateral amygdala of adult rats

“…Notably, the present study differs from the work described above in that our electrophysiological testing occurred after a protracted abstinence period, rather than during acute withdrawal. Studies examining changes to expression of the KOR system have found that dynorphin-B peptide levels were upregulated 21 days following adolescent alcohol exposure (Granholm, Segerstrom, & Nylander, 2018;Lindholm, Ploj, Franck, & Nylander, 2000), but current studies examining long-term changes to KOR function following chronic alcohol exposure are limited. One study examining the role of the KOR system in the alcohol deprivation effect following 18 days of abstinence found that the selective KOR antagonist JDTic reduced the reinstatement of alcohol intake (Uhari-Väänänen et al, 2019), while another found that the KOR system was still actively involved in mediating abstinence-induced stress responsiveness six weeks after chronic alcohol exposure (Gillett, Harshberger, & Valdez, 2013).…”

A history of ethanol intake accelerates the development of morphine analgesic tolerance: A protective potential for omega-3 fatty acids.

“…As for the effects of ethanol on brain function, it activates various receptors and ion channels through several neurotransmitter networks, including the endogenous opioid system (Söderpalm & Ericson, 2011; Trigo et al, 2010). In this respect, there is evidence indicating that episodic exposure of adolescent rats with ethanol alters the level of opioid peptides (dynorphin, B-endorphin, and met-enkephalin) in specific regions underlying pain modulation (Granholm et al, 2018). It is noteworthy that these changes were found to be persistent in some brain areas, such as amygdala, hypothalamus, and pituitary, which may somehow explain the future vulnerability for opioid effect (Granholm et al, 2018).…”

“…In this respect, there is evidence indicating that episodic exposure of adolescent rats with ethanol alters the level of opioid peptides (dynorphin, B-endorphin, and met-enkephalin) in specific regions underlying pain modulation (Granholm et al, 2018). It is noteworthy that these changes were found to be persistent in some brain areas, such as amygdala, hypothalamus, and pituitary, which may somehow explain the future vulnerability for opioid effect (Granholm et al, 2018). These findings raise a possibility that alteration of opioid levels in specific structures may promote the development of analgesic tolerance at cellular levels.…”

“…The protocol of ethanol exposure used in this study (3 g/kg, i.p., 3 days a week, once daily for 4 weeks) has previously been applied in rats (Lauing et al, 2008), and it has been shown to cause blood alcohol concentration of around 300 mg/dl (Nation et al, 1993). This alcohol level meets the criterion of National Institutes of Health for heavy episodic drinking, known as binge consumption in humans (Courtney & Polich, 2009;Granholm et al, 2018). O3 was obtained from commercially available capsules (Danna Pharma Co., Iran) each containing a combination of 120 mg docosahexaenoic acid and 180 mg eicosapentaenoic acid.…”