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Infection rate among intravenous drug users (IDU) is higher than the general public, and is the major cause of morbidity and hospitalization in the IDU population. Epidemiologic studies provide data on increased prevalence of opportunistic bacterial infections such as TB and pneumonia, and viral infections such as HIV-1 and hepatitis in the IDU population. An important component in the intravenous drug abuse population and in patients receiving medically indicated chronic opioid treatment is opioid withdrawal. Data on bacterial virulence in the context of opioid withdrawal suggest that mice undergoing withdrawal had shortened survival and increased bacterial load in response to Salmonella infection. As the body of evidence in support of opioid dependency and its immunosuppressive effects is growing, it is imperative to understand the mechanisms by which opioids exert these effects and identify the populations at risk that would benefit the most from the interventions to counteract opioid immunosuppressive effects. Thus, it is important to refine the existing animal model to closely match human conditions and to cross-validate these findings through carefully controlled human studies. Better understanding of the mechanisms will facilitate the search for new therapeutic modalities to counteract adverse effects including increased infection rates. This review will summarize the effects of morphine on innate and adaptive immunity, identify the role of the mu opioid receptor in these functions and the signal transduction activated in the process. The role of opioid withdrawal in immunosuppression and the clinical relevance of these findings will also be discussed.

Previous studies have shown that morphine abuse during pregnancy cancause a delay in the development of the placenta and embryo and also bring about birth defects. The present study investigates the effect of the duration of maternal morphine consumption during pregnancy, as well as the impacts of morphine abuse on the development of placental layers during the three different periods of pregnancy in Wistar rats. Materials and Methodology. Female Wistar rats have been used in the present study. Experimental groups received morphine (0.05 mg/mL of drinking water) after one night of coupling with male rats for mating. On 9th, 10th, and 14th days of pregnancy, pregnant animals were killed, and placentas were removed and fixed. The cells of the placentas layers were calculated by light microscope and MOTIC and SPSS software. Results. The maternal surface thickness of the placenta was significantly increased, whereasthe fetal surface thickness of placenta was significantly decreased with morphine consumption with a time-dependent manner in experimental groups, compared to control groups. Moreover, the number of trophoblast cells increased in both maternal and fetal surfaces of placenta with respect to the duration of morphine consumption which was overt in the experimental groups compared to the control groups. Conclusion. In general, the time-dependent effects of oral morphine consumption can inhibit the development and natural functioning of cytotrophoblast and syncytiotrophoblast cells of the placental layers.

Background Possible interactions between nervous and immune systems during opioid addiction remain elusive. Recombinant μ–δ opioid receptors (MDOR) and the glutamate receptor 1 (GluR1) subunit of amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors are involved in acute and chronic effects of morphine. Elevated levels of autoantibodies (aAbs) to these receptors were demonstrated in heroin human addicts and in animal models. This study characterized the role of aAbs to these receptors in behavioral modulations recruited during opioid tolerance and sensitization. Methods and findings Male CD-1 mice, immunized with either MDOR or GluR1 peptide fragments (80 μg intraperitoneal (i.p.)), were examined for spontaneous behavior and response to morphine (5 mg/kg i.p.). Spontaneous home-cage activity, novelty-induced self-grooming and morphine-induced hyperactivity were higher in GluR1 mice compared to Vehicle subjects, whereas MDOR immunization was associated with an increased morphine-induced conditioned place preference. In response to escalating doses of morphine (from 10 to 60 mg/kg i.p., twice daily) and naloxone-precipitated withdrawal (1 mg/kg subcutaneous), GluR1 mice exhibited a more marked stereotyped sniffing behavior and less body tremors compared to Vehicle subjects, whereas less sniffing and teeth chattering were found in MDOR mice. The expected downregulation of μ receptor binding sites, induced by chronic morphine in vehicle subjects, was completely absent following MDOR immunization. Conclusions These findings indicate an altered response to morphine-related reinforcing and aversive effects in MDOR mice and altered coping with the environment in GluR1 mice. Circulating aAbs to specific neuroreceptors may alter the response to opiates and play a role as determinants of vulnerability to opiate addiction.

The immune effects of chronic opiate exposure and/or opiate withdrawal are not well understood. The results of human studies with opiate abusers are variable and may not be able to control for important factors such as subjects' drug histories, health and nutritional status. Nonhuman primate models are necessary to control these important factors. A model of opiate dependence in macaques was developed to study the effects of opiate dependence and withdrawal on measures of immune function. Four pigtailed macaques drank a mixture of morphine (20 mg/kg/session) and orange-flavored drink every 6 h for several months. During stable morphine dependence, absolute numbers of neutrophils, monocytes and lymphocytes did not change relative to pre-morphine levels. However, there was a significant decrease in the absolute number and percentage of natural killer (NK) cells in morphine dependence. Either precipitated withdrawal or abstinence for 24 h resulted in behavioral withdrawal signs in all animals. Absolute lymphocyte counts decreased and absolute netrophil counts increased significantly in withdrawal, relative to levels during morphine dependence. Lymphocyte subset (CD4+, CD8+, CD20+) cells were also decreased in absolute numbers with little change in their percentage distributions. There was, however, a significant increase in the percentage of NK cells in withdrawal relative to levels during morphine dependence. This study demonstrates the usefulness of voluntary oral self-dosing procedures for maintaining morphine dependence in nonhuman primates and demonstrates that the morphine withdrawal syndrome includes large alterations in blood parameters of immune system function, including nearly 50% reduction in numbers of CD4+, CD8+ and CD20+ cells.

Heroin addiction, a chronic relapsing disorder characterized by excessive drug taking and seeking, requires constant psychotherapeutic and pharmacotherapeutic interventions to minimize the potential for further abuse. Vaccine strategies against many drugs of abuse are being developed that generate antibodies that bind drug in the bloodstream, preventing entry into the brain and nullifying psychoactivity. However, this strategy is complicated by heroin’s rapid metabolism to 6-acetylmorphine and morphine. We recently developed a “dynamic” vaccine that creates antibodies against heroin and its psychoactive metabolites by presenting multihaptenic structures to the immune system that match heroin’s metabolism. The current study presents evidence of effective and continuous sequestration of brain-permeable constituents of heroin in the bloodstream following vaccination. The result is efficient blockade of heroin activity in treated rats, preventing various features of drugs of abuse: heroin reward, drug-induced reinstatement of drug seeking, and reescalation of compulsive heroin self-administration following abstinence in dependent rats. The dynamic vaccine shows the capability to significantly devalue the reinforcing and motivating properties of heroin, even in subjects with a history of dependence. In addition, targeting a less brain-permeable downstream metabolite, morphine, is insufficient to prevent heroin-induced activity in these models, suggesting that heroin and 6-acetylmorphine are critical players in heroin’s psychoactivity. Because the heroin vaccine does not target opioid receptors or common opioid pharmacotherapeutics, it can be used in conjunction with available treatment options. Thus, our vaccine represents a promising adjunct therapy for heroin addiction, providing continuous heroin antagonism, requiring minimal medical monitoring and patient compliance.

Misuse of opioids is a major comorbidity in people with HIV (PWH). Neurological abnormalities and opioid addiction seen in PWH involve the interplay among signaling pathways. However, the impact of HIV proteins on morphine dependence is understudied. We aimed to understand the modulation of the opioid dependence genes and signaling pathways in the striatum (Str) and prefrontal cortex (PFC) of PWH. HIV-1 transgenic (HIV-1Tg) rats and F344 control animals were given 2 and 4 pellets of morphine (75-mg/pellet)/placebo on Days 1 and 2, respectively, via subcutaneous implantation. On Day 5, at morphine tolerance the rats were sacrificed, Str and PFC were collected for RNA isolation and cDNA preparation. A PCR-array was used to examine the expression of the 65 opioid dependance genes. Varying numbers of genes were significantly upregulated in the Str and PFC of morphine treated rats. Fold change values were uploaded to QIAGEN Ingenuity Pathway Analysis, to study the signaling pathways associated with the treatment conditions. CREB signaling in neurons and Neuroinflammation signaling pathway were highly activated in the Str of both male and female HIV-1Tg rats given morphine. Gαq signaling and S100 family signaling were activated in female HIV-1Tg rats received morphine. Similarly, in the PFC, synthesis of IP3, CREB Signaling in neurons, Gαq signaling in males and CREB Signaling in neuron, and Gαq signaling in females were activated. Using bioinformatic analysis, we identified key signaling pathways and gender dependent changes in the opioid dependent gene expression and pathway enrichment of HIV-1Tg rats at morphine tolerance.

Globally, opioid use disorder (OUD) presents a significant public health challenge linked to high mortality and disability rates. Heroin and other morphine derivatives are prevalent among abused opioids. Prolonged exposure to these substances in individuals with OUD can trigger an immune response, leading to the production of antibodies to morphine that may bind to morphine and potentially mitigate its rewarding effects. In our study, we analyzed serum samples from patients diagnosed with OUD to explore the nature and properties of antibodies to morphine, aiming to characterize the generation of antibodies to morphine due to long-term exposure to morphine. We observed varying titers of antibodies to morphine in OUD patients, absent in healthy controls, with both free morphine and morphine complexes detected bound to these antibodies, indicating less potency. Furthermore, our analysis revealed elevated levels of FoxP3, a critical transcription factor in regulatory T-cells (Tregs) responsible for maintaining immunosuppression. Concurrently, reduced levels of inducible nitric oxide synthase (iNOS) and interleukin-6 (IL-6) indicated immunosuppressive activity. Notably, decreased antibody titers against the Acr1 protein of suggested that morphine-induced immune suppression might compromise responses to other pathogens. These findings indicate that chronic morphine exposure not only suppresses host immunity but also induces the production of antibodies to morphine. Investigating whether these antibodies contribute to immune suppression or can be harnessed to combat morphine dependence presents an intriguing avenue for future research.

Background Mitochondrial dynamics in neurons accompanied by neuroinflammation has been proved as pivotal events during repeated morphine exposure, however, the relationship between mitochondrial dynamics and neuroinflammation still remains unknown. Methods This study was designed to investigate the potential role of astrocyte Drp1 in neuroinflammation during morphine addiction. Nucleus accumbens (NAc) tissues were collected for immunofluorescence, transmission electron microscopy (TEM) and quantitative real-time polymerase chain reaction (qRT-PCR) to detect the expression of pro-inflammatory cytokines and mitochondrial fission proteins. Morphine-induced conditioned place preference (CPP) and open field test (OFT) were used to determine the effects of Mdivi-1, a selective inhibitor of mitochondrial fission protein Drp1 in the rewarding properties of morphine. Astrocyte-specific knockdown experiments by an adeno-associated virus (AAV) vector containing shRNADrp1–EGFP infusion were performed to determine the effects of astrocyte Drp1 in NAc of mice with morphine treatment. Results In this study, we found that repeated morphine exposure induced mitochondrial fragmentation in neurons, astrocytes, and microglia in NAc, correlating with increased inflammatory markers and addictive behaviors. The application of Mdivi-1 effectively mitigated mitochondrial fragmentation and astrocyte-mediated neuroinflammation within the NAc, thereby alleviating morphine-induced addictive behaviors. Crucially, the astrocyte-specific knockdown of Drp1 in NAc significantly curtailed drug-seeking behavior and substantially reduced neuroinflammation. Conclusions Collectively, our findings suggest that alterations in mitochondrial dynamics, particularly within astrocytes, play an important role in regulating neuroinflammation associated with morphine addiction. This research offers novel insights into potential therapeutic strategies for addressing substance use disorder (SUD) by regulating mitochondrial dynamics within astrocyte.

Increasing preclinical evidence demonstrates that dopamine D3 receptor (D3R) antagonists are a potential option for the treatment of drug addiction. The reinstatement of the addiction can be triggered by environmental stimuli that acquire motivational salience through repeated associations with the drug’s effects. YQA14 is a novel D3R antagonist that has exhibited pharmacotherapeutic efficacy in reducing cocaine and amphetamine reward and relapse to drug seeking in mice. In this study we investigated the effects of YQA14 on morphine-induced context-specific locomotor sensitization in mice. We showed that repeated injection of YQA14 (6.25–25 mg/kg every day ip) prior to morphine (10 mg/kg every day sc) not only inhibited the acquisition, but also significantly attenuated the expression of morphine-induced locomotor sensitization. Furthermore, in the expression phase, one single injection of YQA14 (6.25–25 mg/kg, ip) dose-dependently inhibited the expression of morphine-induced behavioral sensitization. Moreover, YQA14 inhibited the expression of morphine-induced behavioral sensitization in wild mice (WT), but not in D3R knockout (D3R −/− ) mice in the expression phase. In addition, D3R −/− mice also displayed the reduction in the expression phase compared with WT mice. In summary, this study demonstrates that blockade or knockout of the D3R inhibits morphine-induced behavior sensitization, suggesting that D3R plays an important role in the pathogenesis and etiology of morphine addiction, and it might be a potential target for clinical management of opioid addiction.

•Hydrolytically stable haptens induced antibodies both to heroin and its metabolites.•Facial recognition of a heroin-like hapten was achieved by induced antibodies.•Facial recognition of a morphine-like hapten was achieved by induced antibodies.•High titers of antibodies were achieved with liposomal lipid A as adjuvant.•Antibodies to both stable haptens inhibited the effects of heroin injected in mice. Novel synthetic compounds similar to heroin and its major active metabolites, 6-acetylmorphine and morphine, were examined as potential surrogate haptens for the ability to interface with the immune system for a heroin vaccine. Recent studies have suggested that heroin-like haptens must degrade hydrolytically to induce independent immune responses both to heroin and to the metabolites, resulting in antisera containing mixtures of antibodies (type 2 cross-reactivity). To test this concept, two unique hydrolytically stable haptens were created based on presumed structural facial similarities to heroin or to its active metabolites. After conjugation of a heroin-like hapten (DiAmHap) to tetanus toxoid and mixing with liposomes containing monophosphoryl lipid A, high titers of antibodies after two injections in mice had complementary binding sites that exhibited strong type 1 (“true”) specific cross-reactivity with heroin and with both of its physiologically active metabolites. Mice immunized with each surrogate hapten exhibited reduced antinociceptive effects caused by injection of heroin. This approach obviates the need to create hydrolytically unstable synthetic heroin-like compounds to induce independent immune responses to heroin and its active metabolites for vaccine development. Facial recognition of hydrolytically stable surrogate haptens by antibodies together with type 1 cross-reactivities with heroin and its metabolites can help to guide synthetic chemical strategies for efficient development of a heroin vaccine.