Blocking IL-17A prevents oxycodone-induced depression-like effects and elevation of IL-6 levels in the ventral tegmental area and reduces oxycodone-derived physical dependence in rats.

Oxycodone is the most prescribed opioid for pain management and has been available in clinics for almost a century, but effects of chronic oxycodone have been studied less than morphine in preclinical and clinical studies. Newly developed depression has been coupled with chronic oxycodone use in a few clinical studies, but no preclinical studies have investigated the pathogenesis of oxycodone-induced depression. Gut microbiome changes following oxycodone use is an understudied area, and interleukin-17A (IL-17A) is linked to both the development of mood disorders and regulation of gut microbiome.

Cyanidin prevents MDPV withdrawal-induced anxiety-like effects and dysregulation of cytokine systems in rats.

Psychostimulant exposure and withdrawal cause neuroimmune dysregulation and anxiety that contributes to dependence and relapse. Here, we tested the hypothesis that withdrawal from the synthetic cathinone MDPV (methylenedioxypyrovalerone) produces anxiety-like effects and enhanced levels of mesocorticolimbic cytokines that are inhibited by cyanidin, an anti-inflammatory flavonoid and nonselective blocker of IL-17A signaling. For comparison, we tested effects on glutamate transporter systems that are also dysregulated during psychostimulant free period.

Preclinical and clinical evidence for suppression of alcohol intake by apremilast.

Treatment options for alcohol use disorders (AUDs) have minimally advanced since 2004, while the annual deaths and economic toll have increased alarmingly. Phosphodiesterase type 4 (PDE4) is associated with alcohol and nicotine dependence. PDE4 inhibitors were identified as a potential AUD treatment using a bioinformatics approach.

Potentiation of morphine antinociception and inhibition of diabetic neuropathic pain by the multi-chemokine receptor antagonist peptide RAP-103.

Aims: We determined the ability of the multi-chemokine receptor (CCR2/CCR5/CCR8) antagonist RAP-103 to modulate pain behaviors in an acute model of surgical pain, with and without an added opioid (morphine), and by itself in a chronic model of Streptozotocin (STZ)-induced diabetic peripheral neuropathy (DPN).

Materials And Methods: Pain behaviors were assessed by mechanical and thermal tests in rats. Cytokine and chemokine biomarkers in sciatic nerve and spinal cord were assessed by in situ qPCR.

A Cannabinoid 2-Selective Agonist Inhibits Allogeneic Skin Graft Rejection .

Previous work from our laboratory showed that a CB2 selective agonist, O-1966, blocked the proliferative response of C57BL/6 mouse spleen cells exposed to spleen cells of C3HeB/FeJ mice in the mixed lymphocyte reaction (MLR). The MLR is widely accepted as an correlate of grant rejection. Mechanisms of the immunosuppression induced by the cannabinoid were explored, and it was shown that O-1966 in this assay induced CD25Foxp3 Treg cells and IL-10, as well as down-regulated mRNA for CD40 and the nuclear form of the transcription factors NF-κB and NFAT in T-cells.

Artificial Intelligence Identified Resilient and Vulnerable Female Rats After Traumatic Stress and Ethanol Exposure: Investigation of Neuropeptide Y Pathway Regulation.

Post-traumatic stress disorder (PTSD) is initiated by traumatic-stress exposure and manifests into a collection of symptoms including increased anxiety, sleep disturbances, enhanced response to triggers, and increased sympathetic nervous system arousal. PTSD is highly co-occurring with alcohol use disorder. Only some individuals experiencing traumatic stress develop PTSD and a subset of individuals with PTSD develop co-occurring alcohol use disorder.

Chemokine receptor antagonists enhance morphine's antinociceptive effect but not respiratory depression.

Aims: We have shown that chemokines injected into the periaqueductal gray region of the brain blocks opioid-induced analgesia in the rat cold-water tail flick test (CWTF). The present experiments tested whether chemokine receptor antagonists (CRAs), in combination with sub-analgesic doses of morphine, would provide maximal analgesia in the CWTF test and the mouse formalin pain assay. The effect of CRAs on respiratory depression was also evaluated.

Chemokine Receptor Antagonists in Combination with Morphine as a Novel Strategy for Opioid Dose Reduction in Pain Management.

Introduction: Although opioids are widely prescribed for pain, in many circumstances, they have only modest efficacy. Preclinical studies have shown that chemokines, immune mediators released during tissue injury and inflammation, can desensitize opioid receptors and block opioid analgesia by a process termed "heterologous desensitization." The present studies tested the hypothesis that in evoked pain, certain chemokine receptor antagonists (CRAs), given with a submaximal dose of morphine, would result in enhanced morphine potency.

Opioid-sparing effects of cannabinoids on morphine analgesia: participation of CB and CB receptors.

Background And Purpose: Much of the opioid epidemic arose from abuse of prescription opioid drugs. This study sought to determine if the combination of a cannabinoid with an opioid could produce additive or synergistic effects on pain, allowing reduction in the opioid dose needed for maximal analgesia.

Experimental Approach: Pain was assayed using the formalin test in mice and the carrageenan assay in rats.

Ethyl Pyruvate Modulates Murine Dendritic Cell Activation and Survival Through Their Immunometabolism.

Attenuating the innate immunity activation could ameliorate inflammation and disease in settings such as transplant rejection or autoimmunity. Recently, a pivotal role for metabolic re-programming in TLR-induced dendritic cell (DC) activation has emerged. Ethyl pyruvate (EP), a pyruvate derivative, possesses anti-inflammatory properties and in animal models of disease.

Coadministration of Chemokine Receptor Antagonists with Morphine Potentiates Morphine's Analgesic Effect on Incisional Pain in Rats.

Crossdesensitization between opioid and chemokine receptors and involvement of chemokines in pain modulation are well established. We investigated if coadministration of chemokine receptor antagonists (CRAs) with morphine would enhance the analgesic potency of morphine on incisional pain in rats. Animals underwent incisional surgery on the left hind paw and pain responses were evaluated using von Frey filaments at various time points postsurgery between 15 and 360 minutes and daily between 24 and 72 hours.

A CB2-Selective Cannabinoid Suppresses T-Cell Activities and Increases Tregs and IL-10.

We have previously shown that agonists selective for the cannabinoid receptor 2 (CB2), including O-1966, inhibit the Mixed Lymphocyte Reaction (MLR), an in vitro correlate of organ graft rejection, predominantly through effects on T-cells. Current studies explored the mechanism of this immunosuppression by O-1966 using mouse spleen cells. Treatment with O-1966 dose-relatedly decreased levels of the active nuclear forms of the transcription factors NF-κB and NFAT in wild-type T-cells, but not T-cells from CB2 knockout (CB2R k/o) mice.

Effects of Cannabinoids on T-cell Function and Resistance to Infection.

This review examines the effects of cannabinoids on immune function, with a focus on effects on T-cells, as well as on resistance to infection. The paper considers the immune modulating capacity of marijuana, of ∆(9)-THC extracted from the marijuana plant, and synthetic cannabinoids. Of particular interest are synthetic compounds that are CB2 receptor (CB2R) selective agonists.

Gene x environment interactions impact endometrial function and the menstrual cycle: PROGINS, life history, anthropometry, and physical activity.

Objectives: We assessed the impact of a high frequency, functionally significant allelic variant of the progesterone receptor gene (PROGINS) on endometrial function and menstrual cycle characteristics. Further we asked whether PROGINS moderates the impact of life history characteristics, anthropometric measures, and physical activity on endometrial function.

Methods: Fifty-two women were genotyped for the PROGINS variant, provided life history information, and had anthropometric measurements made.

Cannabinoids inhibit T-cells via cannabinoid receptor 2 in an in vitro assay for graft rejection, the mixed lymphocyte reaction.

Cannabinoids are known to have anti-inflammatory and immunomodulatory properties. Cannabinoid receptor 2 (CB2) is expressed mainly on leukocytes and is the receptor implicated in mediating many of the effects of cannabinoids on immune processes. This study tested the capacity of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and of two CB2-selective agonists to inhibit the murine Mixed Lymphocyte Reaction (MLR), an in vitro correlate of graft rejection following skin and organ transplantation.

Morphine, but not trauma, sensitizes to systemic Acinetobacter baumannii infection.

Acinetobacter baumannii is an important nosocomial pathogen in civilian intensive care units. Recently the incidence has increased in wounded military personnel. Morphine is documented in numerous animal studies to be immunosuppressive and to sensitize to infection.

Innate immune responses to systemic Acinetobacter baumannii infection in mice: neutrophils, but not interleukin-17, mediate host resistance.

Acinetobacter baumannii is a nosocomial pathogen with a high prevalence of multiple-drug-resistant strains, causing pneumonia and sepsis. The current studies further develop a systemic mouse model of this infection and characterize selected innate immune responses to the organism. Five clinical isolates, with various degrees of antibiotic resistance, were assessed for virulence in two mouse strains, and between male and female mice, using intraperitoneal infection.

Potentiating effect of morphine on oral Salmonella enterica serovar Typhimurium infection is μ-opioid receptor-dependent.

Previous studies from our laboratory demonstrated that mice treated with morphine pellets are sensitized to Salmonella enterica, serovar Typhimurium infection. However, the opioid receptor antagonist, naltrexone, only partially blocked the effect of morphine, raising the possibility that the opioid might have some of its effects through a nonopioid receptor. To further clarify whether sensitization to infection is an opioid receptor-dependent phenomenon, μ-opioid receptor knockout (MORKO) mice were used in the present study.

Nociceptin/orphanin FQ suppresses adaptive immune responses in vivo and at picomolar levels in vitro.

Nociceptin/orphanin FQ (N/OFQ), added in vitro to murine spleen cells in the picomolar range, suppressed antibody formation to sheep red blood cells in a primary and a secondary plaque-forming cell assay. The activity of the peptide was maximal at 10(-12) M, with an asymmetric U-shaped dose-response curve that extended activity to 10(-14) M. Suppression was not blocked by pretreatment with naloxone.

Endomorphin 1 and endomorphin 2 suppress in vitro antibody formation at ultra-low concentrations: anti-peptide antibodies but not opioid antagonists block the activity.

Endomorphin 1 (EM-1) and endomorphin 2 (EM-2) were tested for their capacity to alter immune function. Addition of either of these peptides to murine spleen cells in vitro inhibited antibody formation to sheep red blood cells in a bi-phasic dose dependent manner. Maximal inhibition was achieved at doses in the range of 10(-13) to 10(-15)M.

Effects of opioid tolerance and withdrawal on the immune system.

Review of the robust literature using acute drug injection paradigms points clearly to the conclusion that morphine is immunosuppressive. In contrast, studies of the effect of subacute or chronic administration of morphine on immune function is limited, with variable results. In some cases tolerance to the immunosuppressive effects of the drug is clearly demonstrated, but in other cases, selected immune parameters do not demonstrate tolerance.

Anandamide and Delta9-tetrahydrocannabinol directly inhibit cells of the immune system via CB2 receptors.

This study shows that two cannabinoids, Delta(9)-tetrahydrocannabinol (THC) and anandamide, induce dose-related immunosuppression in both the primary and secondary in vitro plaque-forming cell assays of antibody formation. The immunosuppression induced by both compounds could be blocked by SR144528, an antagonist specific for the CB(2) receptor, but not by SR141716, a CB(1) antagonist. These studies are novel in that they show that both anandamide and THC are active in the nanomolar to picomolar (for anandamide) range in these assays of immune function, and that both mediate their effects directly on cells of the immune system through the CB(2) receptor.

A novel role of cannabinoids: implication in the fever induced by bacterial lipopolysaccharide.

There is continuing interest in elucidating the actions of drugs of abuse on the immune system and on infection. The present study investigated the effects of the cannabinoid (CB) receptor agonist aminoalkylindole, (+)-WIN 55,212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], on fever produced after injection of lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, the best known and most frequently used experimental model. Intraperitoneal injection of LPS (50 mug/kg) induced a biphasic fever, with the first peak at 180 min and the second at 300 min postinjection.