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.

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.