Sex and chronic stress differentially alter phosphorylated mu and delta opioid receptor levels in the rat hippocampus following oxycodone conditioned place preference

Bellamy, Julia R.; Rubin, Batsheva R.; Zverovich, Angelica; Zhou, Yan; Contoreggi, Natalina H.; Gray, Jason D.; McEwen, Bruce S.; Kreek, Mary Jeanne; Milner, Teresa A.

doi:10.1016/j.neulet.2019.134514

Cited by 13 publications

(30 citation statements)

References 31 publications

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“…In agreement with prior studies (Bellamy et al., 2019; Gonzales et al., 2011; Milner, McEwen, & Waters, 2014), diffuse pMOR‐ir was found primarily in SLu of CA3a and b, and to a lesser extent in SO, PCL and SR of these regions (Figure 7a,b). There were no significant differences in the optical density of MOR‐ir in any of lamina of CA3a or CA3b in Sal‐injected males compared to Sal‐injected females (Figure 7c,d).…”

Section: Resultssupporting

confidence: 92%

“…Thus, together with prior studies (Bellamy et al., 2019), the present results demonstrate that Sal‐injections, with or without behavior, do not alter the baseline levels of pMOR in the CA3 region in either males or females. Importantly, in contrast to Oxy CPP, Oxy‐injections alone did not increase pMOR in the CA3 region of either sex.…”

Section: Resultssupporting

confidence: 85%

“…The antibodies described below are the same as those employed in previous light and EM studies (Bellamy et al., 2019; Mazid et al., 2016; Milner et al., 2013; Pierce, Kelter, McEwen, Waters, & Milner, 2014; Reich et al, 2019; Ryan et al., 2018).…”

Section: Methodsmentioning

confidence: 99%

“…Our previous studies demonstrated that both female and male Sprague Dawley rats acquired conditioning place preference (CPP) to the mu opioid receptor (MOR) agonist Oxy and that this results in sex‐specific alterations in the hippocampal opioid system (Bellamy et al., 2019; Randesi et al., 2019; Ryan et al., 2018). Notably, following Oxy CPP delta opioid receptors (DOR) redistributed within mossy fiber–CA3 synapses in females and males in a manner similar to that shown to be important for opioid‐mediated LTP in high estrogen females (Harte‐Hargrove et al., 2015; Ryan et al., 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, in Oxy‐females but not Oxy‐males, MORs and DORs were rearranged in hilar interneurons in a manner that could enhance disinhibition of granule cells via two different circuits: (a) plasmalemmal‐associated DORs increased on GABAergic interneuron dendrites (Ryan et al., 2018) which are known to contain neuropeptide Y (NPY) and are important for promoting LTP via the lateral perforant pathway (Sperk, Hamilton, & Colmers, 2007a); and (b) plasmalemmal‐associated MORs increased in parvalbumin (PARV)‐labeled dendrites (Ryan et al., 2018) which are known to inhibit granule cell soma (Drake, Chavkin, & Milner, 2007). These changes in DOR and MOR trafficking following Oxy CPP are accompanied by an upregulation of phosphorylated MOR (pMOR) levels in CA3b in females and phosphorylated DOR (pDOR) levels in CA3a in males (Bellamy et al., 2019). Together, these studies demonstrate that Oxy CPP induces sex‐specific changes in the hippocampal opioid system that would increase excitation and facilitate opioid‐associative learning processes, especially in females.…”

Section: Introductionmentioning

confidence: 99%

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Oxycodone injections not paired with conditioned place preference have little effect on the hippocampal opioid system in female and male rats

Ashirova

Contoreggi

Johnson

et al. 2020

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Oxycodone (Oxy) conditioned place preference (CPP) in Sprague Dawley rats results in sex‐specific alterations in hippocampal opioid circuits in a manner that facilitates opioid‐associative learning processes, particularly in females. Here, we examined if Oxy (3 mg/kg, I.P.) or saline (Sal) injections not paired with behavioral testing similarly affect the hippocampal opioid system. Sal‐injected females compared to Sal‐injected males had: (1) higher densities of cytoplasmic delta opioid receptors (DOR) in GABAergic hilar dendrites suggesting higher baseline reserve DOR pools and (2) elevated phosphorylated DOR levels, but lower phosphorylated mu opioid receptor (MOR) levels in CA3a suggesting that the baseline pools of activated opioid receptors vary in females and males. In contrast to CPP studies, Oxy‐injections in the absence of behavioral tests resulted in few changes in the hippocampal opioid system in either females or males. Specifically, Oxy‐injected males compared to Sal‐injected males had fewer DORs near the plasma membrane of CA3 pyramidal cell dendrites and in CA3 dendritic spines contacted by mossy fibers, and lower pMOR levels in CA3a. Oxy‐injected females compared to Sal‐injected females had higher total DORs in GABAergic dendrites and lower total MORs in parvalbumin‐containing dendrites. Thus, unlike Oxy CPP, Oxy‐injections redistributed opioid receptors in hippocampal neurons in a manner that would either decrease (males) or not alter (females) excitability and plasticity processes. These results indicate that the majority of changes within hippocampal opioid circuits that would promote opioid‐associative learning processes in both females and males do not occur with Oxy administration alone, and instead must be paired with CPP.

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Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 85%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oxycodone injections not paired with conditioned place preference have little effect on the hippocampal opioid system in female and male rats

Ashirova

Contoreggi

Johnson

et al. 2020

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Chronic stress differentially altersmRNAexpression of opioid peptides and receptors in the dorsal hippocampus of female and male rats

et al. 2021

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Chronic immobilization stress (CIS) results in sex‐dependent changes in opioid peptide levels and receptor subcellular distributions within the rat dorsal hippocampus, which are paralleled with an inability for males to acquire conditioned place preference (CPP) to oxycodone. Here, RNAScope in situ hybridization was used to determine the expression of hippocampal opioid peptides and receptors in unstressed (US) and CIS estrus female and male adult (∼2.5 months old ) Sprague Dawley rats. In all groups, dentate granule cells expressed PENK and PDYN; additionally, numerous interneurons expressed PENK. OPRD1 and OPRM1 were primarily expressed in interneurons, and to a lesser extent, in pyramidal and granule cells. OPRK1‐was expressed in sparsely distributed interneurons. There were few baseline sex differences: US females compared to US males had more PENK‐expressing and fewer OPRD1‐expressing granule cells and more OPRM1‐expressing CA3b interneurons. Several expression differences emerged after CIS. Both CIS females and males compared to their US counterparts had elevated: (1) PENK‐expressing dentate granule cells and interneurons in CA1 and CA2/3a; (2) OPRD1 probe number and cell expression in CA1, CA2/3a and CA3b and the dentate gyrus; and (3) OPRK1‐expressing interneurons in the dentate hilus. Also, CIS males compared to US males had elevated: (1) PDYN expression in granule cells; (2) OPRD1 probe and interneuron expression in CA2/3a; (3) OPRM1 in granule cells; and (4) OPRK1 interneuron expression in CA2/3a. The sex‐specific changes in hippocampal opioid gene expression may impact network properties and synaptic plasticity processes that may contribute to the attenuation of oxycodone CPP in CIS males.

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Acute Delta 9‐tetrahydrocannabinol administration differentially alters the hippocampal opioid system in adult female and male rats

Windisch

Mazid

Johnson

et al. 2021

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Our prior studies demonstrated that the rat hippocampal opioid system can undergo sex‐specific adaptations to external stimuli that can influence opioid‐associated learning processes. This opioid system extensively overlaps with the cannabinoid system. Moreover, acute administration of Δ9Tetrahydrocannabinoid (THC), the primary psychoactive constituent of cannabis, can alter cognitive behaviors that involve the hippocampus. Here, we use light and electron microscopic immunocytochemical methods to examine the effects of acute THC (5 mg/kg, i.p., 1 h) on mossy fiber Leu‐Enkephalin (LEnk) levels and the distribution and phosphorylation levels of delta and mu opioid receptors (DORs and MORs, respectively) in CA3 pyramidal cells and parvalbumin dentate hilar interneurons of adult female and male Sprague–Dawley rats. In females with elevated estrogen states (proestrus/estrus stage), acute THC altered the opioid system so that it resembled that seen in vehicle‐injected females with low estrogen states (diestrus) and males: (1) mossy fiber LEnk levels in CA2/3a decreased; (2) phosphorylated‐DOR levels in CA2/3a pyramidal cells increased; and (3) phosphorylated‐MOR levels increased in most CA3b laminae. In males, acute THC resulted in the internalization of MORs in parvalbumin‐containing interneuron dendrites which would decrease disinhibition of granule cells. In both sexes, acute THC redistributed DORs to the near plasma membrane of CA3 pyramidal cell dendrites, however, the dendritic region varied with sex. Additionally, acute THC also resulted in a sex‐specific redistribution of DORs within CA3 pyramidal cell dendrites which could differentially promote synaptic plasticity and/or opioid‐associated learning processes in both females and males.

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Sex and chronic stress differentially alter phosphorylated mu and delta opioid receptor levels in the rat hippocampus following oxycodone conditioned place preference

Cited by 13 publications

References 31 publications

Oxycodone injections not paired with conditioned place preference have little effect on the hippocampal opioid system in female and male rats

Oxycodone injections not paired with conditioned place preference have little effect on the hippocampal opioid system in female and male rats

Chronic stress differentially altersmRNAexpression of opioid peptides and receptors in the dorsal hippocampus of female and male rats

Acute Delta 9‐tetrahydrocannabinol administration differentially alters the hippocampal opioid system in adult female and male rats

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