Chronic Opioid Administration Research Articles

Targeting mitochondrial dynamics of morphine-responsive dopaminergic neurons ameliorates opiate withdrawal.

Converging studies demonstrate the dysfunction of the dopaminergic neurons following chronic opioid administration. However, the therapeutic strategies targeting opioid-responsive dopaminergic ensembles that contribute to the development of opioid withdrawal remain to be elucidated. Here, we used the neuronal activity-dependent Tet-Off system to label dopaminergic ensembles in response to initial morphine exposure (Mor-Ens) in the ventral tegmental area (VTA). Fiber optic photometry recording and transcriptome analysis revealed downregulated spontaneous activity and dysregulated mitochondrial respiratory, ultrastructure, and oxidoreductase signal pathways after chronic morphine administration in these dopaminergic ensembles. Mitochondrial fragmentation and the decreased mitochondrial fusion gene mitofusin 1 (Mfn1) were found in these ensembles after prolonged opioid withdrawal. Restoration of Mfn1 in the dopaminergic Mor-Ens attenuated excessive oxidative stress and the development of opioid withdrawal. Administration of Mdivi-1, a mitochondrial fission inhibitor, ameliorated the mitochondrial fragmentation and maladaptation of the neuronal plasticity in these Mor-Ens, accompanied by attenuated development of opioid withdrawal after chronic morphine administration, without affecting the analgesic effect of morphine. These findings highlighted the plastic architecture of mitochondria as a potential therapeutic target for opioid analgesic-induced substance use disorders.

Cytokines in hepatitis C-infected patients with or without opioid maintenance therapy.

Both chronic hepatitis C virus (HCV) infection and opioids cause altered blood levels of cytokines. Previous studies have investigated levels of selected groups of cytokines in patients on opioid maintenance treatment. Little is known about the levels of multiple cytokines in patients with chronic HCV infection on opioid maintenance treatment. Our aim was to investigate the cytokine profile in patients with active HCV infection with and without opioid maintenance treatment. We conducted a cross-sectional study in an out-patients population included upon referral for antiviral hepatitis C infection treatment. The level of 27 cytokines was measured in serum using multiplex technology. Patients were interviewed using a modified version of the European addiction severity index. Data pertaining to weight, height, current medication, smoking habits, allergies, previous medical history and ongoing withdrawal symptoms were collected. Non-parametric testing was used to investigate differences in levels of cytokines between the two groups. A 3-model hierarchical regression analysis was used to analyse associations between cytokines and confounding variables. Out of 120 included patients, 53 were on opioid maintenance treatment. Median duration of opioid treatment was 68.4 months. There were no demographical differences between the two groups other than age. IL-1β was lower and eotaxin-1 higher in the group on opioid maintenance treatment than in the non-opioid group. No other inter-group differences in the remaining cytokine levels were found. In HCV infection patients, the impact of chronic opioid administration on peripheral circulating cytokine level is minimal.

Behavioral mechanisms of oxycodone's effects in female and male rats: Reinforcement delay and impulsive choice.

μ-Opioid agonists (e.g., morphine) typically increase impulsive choice, which has been interpreted as an opioid-induced increase in sensitivity to reinforcement delay. Relatively little research has been done with opioids other than morphine (e.g., oxycodone), or on sex differences in opioid effects, on impulsive choice. The present study investigated the effects of acute (0.1-1.0 mg/kg) and chronic (1.0 mg/kg twice/day) administration of oxycodone on choice controlled by reinforcement delay, a primary mechanism implicated in impulsive choice, in female and male rats. Rats responded under a concurrent-chains procedure designed to quantify the effects of reinforcement delay on choice within each session. For both sexes, choice was sensitive to delay under this procedure. Sensitivity to delay under baseline was slightly higher for males than females, suggesting more impulsive choice with males. When given acutely, intermediate and higher doses of oxycodone decreased sensitivity to delay; this effect was larger and more reliable in males than females. When given chronically, sex differences were also observed: tolerance developed to the sensitivity-decreasing effects in females, whereas sensitization developed in males. These data suggest that reinforcement delay may play an important role in sex differences in impulsive choice, as well as in the effects of acute and chronic administration of opioids in impulsive choice. However, drug-induced changes in impulsive choice could be related to at least two potential behavioral mechanisms: reinforcement delay and/or reinforcement magnitude. Effects of oxycodone on sensitivity to reinforcement magnitude remain to be fully characterized. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Repurposing EGFR Inhibitors for Oral Cancer Pain and Opioid Tolerance.

Oral cancer pain remains a significant public health concern. Despite the development of improved treatments, pain continues to be a debilitating clinical feature of the disease, leading to reduced oral mobility and diminished quality of life. Opioids are the gold standard treatment for moderate-to-severe oral cancer pain; however, chronic opioid administration leads to hyperalgesia, tolerance, and dependence. The aim of this review is to present accumulating evidence that epidermal growth factor receptor (EGFR) signaling, often dysregulated in cancer, is also an emerging signaling pathway critically involved in pain and opioid tolerance. We presented preclinical and clinical data to demonstrate how repurposing EGFR inhibitors typically used for cancer treatment could be an effective pharmacological strategy to treat oral cancer pain and to prevent or delay the development of opioid tolerance. We also propose that EGFR interaction with the µ-opioid receptor and glutamate N-methyl-D-aspartate receptor could be two novel downstream mechanisms contributing to pain and morphine tolerance. Most data presented here support that repurposing EGFR inhibitors as non-opioid analgesics in oral cancer pain is promising and warrants further research.

Short-chain fatty acid, butyrate prevents morphine-and paclitaxel-induced nociceptive hypersensitivity

Nociceptive hypersensitivity is a significant side effect with the chronic administration of opioids as well as chemotherapeutics. Both opioid-induced hypersensitivity (OIH) and chemotherapy-induced hypersensitivity (CIH) are characterized by an increased sensitivity to painful stimuli which can significantly reduce the quality of life for individuals on either drug(s). Here we demonstrate the nociceptive hypersensitivity associated with repeated administration of morphine (opioid) and paclitaxel (chemotherapeutic) treatment can be reversed by oral supplementation with the short-chain fatty acid (SCFA) sodium butyrate (NaBut). In two separate mouse behavioral models for nociceptive hypersensitivity, we found that thermal hyperalgesia (for OIH) and cold allodynia (for CIH) were prevented by treatment with oral butyrate (p.o, b.i.d). Electrophysiological recordings of small diameter dorsal root ganglia (DRG) neurons from morphine and paclitaxel treated mice showed an increase in neuronal hyperexcitability in both drug models which was likewise prevented by oral butyrate treatment. Using colonic conditioned media obtained from excised colon segments we found that gut mediators of morphine treated mice can induce hyperexcitability in naïve DRG neurons, but such enhanced excitability is not present when animals are co-treated with NaBut suggesting gut derived mediators modulate neuronal hyperexcitability. In-vitro NaBut treatment did not prevent morphine-induced excitability, suggesting an indirect role of butyrate in modulating neuronal hypersensitivity. These data taken together suggest that gut derived mediators affect opioid and chemotherapeutic-induced neuronal hypersensitivity that is prevented by the SCFA butyrate.

Adverse Effects of Repeated, Intravenous Morphine on Recovery after Spinal Cord Injury in Young, Male Rats Are Blocked by a Kappa Opioid Receptor Antagonist.

Immediately following spinal cord injury (SCI) patients experience pain associated with injury to the spinal cord and nerves as well as with accompanying peripheral injuries. This pain is usually treated with opioids, and most commonly with morphine. However, in a rodent model we have shown that, irrespective of the route of administration, morphine administered in the acute phase of SCI undermines long-term locomotor recovery. Our previous data suggest that activation of kappa opioid receptors (KORs) mediates these negative effects. Blocking KORs with norbinaltorphimine (norBNI), prior to a single dose of epidural morphine, prevented the morphine-induced attenuation of locomotor recovery. Because numerous cellular changes occur with chronic opioid administration compared with a single dose, the current study tested whether norBNI was also effective in a more clinically relevant paradigm of repeated, intravenous morphine administration after SCI. We hypothesized that blocking KOR activation during repeated, intravenous morphine administration would also protect recovery. Supporting this hypothesis, we found that blocking KOR activation in young, male rats prevented the negative effects of morphine on locomotor recovery, although neither norBNI nor morphine had an effect on long-term pain at the doses used. We also found that norBNI treatment blocked the adverse effects of morphine on lesion size. These data suggest that a KOR antagonist given in conjunction with morphine may provide a clinical strategy for effective analgesia without compromising locomotor recovery after SCI.

Morphine and high-fat diet differentially alter the gut microbiota composition and metabolic function in lean versus obese mice

There are known associations between opioids, obesity, and the gut microbiome, but the molecular connection/mediation of these relationships is not understood. To better clarify the interplay of physiological, genetic, and microbial factors, this study investigated the microbiome and host inflammatory responses to chronic opioid administration in genetically obese, diet-induced obese, and lean mice. Samples of feces, urine, colon tissue, and plasma were analyzed using targeted LC-MS/MS quantification of metabolites, immunoassays of inflammatory cytokine levels, genome-resolved metagenomics, and metaproteomics. Genetic obesity, diet-induced obesity, and morphine treatment in lean mice each showed increases in distinct inflammatory cytokines. Metagenomic assembly and binning uncovered over 400 novel gut bacterial genomes and species. Morphine administration impacted the microbiome’s composition and function, with the strongest effect observed in lean mice. This microbiome effect was less pronounced than either diet or genetically driven obesity. Based on inferred microbial physiology from the metaproteome datasets, a high-fat diet transitioned constituent microbes away from harvesting diet-derived nutrients and towards nutrients present in the host mucosal layer. Considered together, these results identified novel host-dependent phenotypes, differentiated the effects of genetic obesity versus diet induced obesity on gut microbiome composition and function, and showed that chronic morphine administration altered the gut microbiome.

Effect of Preoperative Chronic Opioid Use on Mortality and Morbidity in Vascular Surgical Patients

IntroductionOpioid derivates are an essential part of everyday clinical pain management practice. They have excellent analgesic, sedative, and sympatholytic effects and are widely used in various conditions. Beyond advantageous aspects, there are numerous problems with the chronic use of these agents. Dependency and life-threatening complications are the biggest problems with both illegal and prescribed opioid derivates. In our current study, effects of chronic opioid use were observed on mortality and life quality in the case of vascular surgery.MethodsThis prospective, observational study was conducted between 2014 and 2017. After obtaining informed consent, all participants were asked to fill a questionnaire containing different psychological tests. Perioperative data, chronic medical therapy, and anthropometric data were also collected. Opioid user and non-user patients’ psychological results were compared with non-parametrical tests. The effect of chronic opioid administration was investigated with logistic regression method with bootstrapping.ResultsFinally, the data of 164 patients were analyzed. 64.0% of participants were male, the mean age was 67.05 years, and the standard deviation was 9.48 years. The median follow-up time was 1312 days [interquartile range (IQR): 930-1582 days]. During the follow-up time, 42 patients died (25.6%). In the examined patient cohort, the frequency of opioid derivate use was 3.7% (only six patients). In the non-survived group, opioid use was significantly higher (1.6% vs. 9.5%, p=0.019). Significant differences were found in the aspect of cognitive performance measured by Mini-Mental State Examination (MMSE), opioid users have had lower points [25.5 (IQR: 24.5-26.0) vs. 28.0 (IQR: 27.0-29.0) p=0.008]. Opioid users have showed higher score on Beck Depression Inventory (BDI) [15.5 (IQR: 10.0-18.0) vs. 6.0 (IQR: 3.0-11.0), p=0.030). In a multivariate Cox regression model built up from registered preoperative medical treatment, opioids were found as a risk factor for all-cause mortality [adjusted hazard ratio (AHR): 4.31, 95% CI: 1.77-10.55, p=0.001].ConclusionOur current findings suggest that chronic, preoperative use of opioids could associate with increased mortality. Furthermore, both decrease in cognitive performance and increased depression symptoms were found in the opioid user cohorts which emphasize the importance of further risk stratification of these patients.

Remote local photoactivation of morphine produces analgesia without opioid-related adverse effects.

Opioid-based drugs are the gold standard medicines for pain relief. However, tolerance and several side effects (i.e. constipation and dependence) may occur upon chronic opioid administration. Photopharmacology is a promising approach to improve the benefit/risk profiles of these drugs. Thus, opioids can be locally activated with high spatiotemporal resolution, potentially minimizing systemic-mediated adverse effects. Here, we aimed at developing a morphine photo-derivative (photocaged morphine), which can be activated upon light irradiation both in vitro and in vivo. Light-dependent activity of pc-morphine was assessed in cell-based assays (intracellular calcium accumulation and electrophysiology) and in mice (formalin animal model of pain). In addition, tolerance, constipation and dependence were investigated in vivo using experimental paradigms. In mice, pc-morphine was able to elicit antinociceptive effects, both using external light-irradiation (hind paw) and spinal cord implanted fibre-optics. In addition, remote morphine photoactivation was devoid of common systemic opioid-related undesired effects, namely, constipation, tolerance to the analgesic effects, rewarding effects and naloxone-induced withdrawal. Light-dependent opioid-based drugs may allow effective analgesia without the occurrence of tolerance or the associated and severe opioid-related undesired effects. This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Modulatory effect of opioid administration on the activity of cholinesterase enzyme: a systematic review of mice/rat models

We aimed to review the literature to find the specific effect of opioids on the activity of cholinesterase (ChE) enzyme which plays a substantial role in the functioning of cholinergic system. Literature search was performed by two independent reviewers in order to find relevant articles about the changes in the activity of ChE in mice or rat following opioid administration. Based on findings from literature review, opioid administration is able to induce cholinergic modulation via decreasing or increasing the activity of ChE enzyme. However, the degree of variation of ChE in various brain regions is different. No gender differences was reported in the effect of opioids on ChE activity. Although chronic opioid administration may decrease enzyme function, ChE activity might be unchanged following opioid withdrawal using naloxone or the development of tolerance. Opioid type affects whether or not naloxone can reverse the changes of ChE. Direct inhibitory action of morphine and the other opioid ligands believed responsible for the decrease in the ChE activity. Moreover, the potency of codeine to induce allosteric enhancement of acetylcholine receptor signaling might be involved in the cholinergic modulation of codeine and other opioids. Animal studies on rat and mice showed that opioids may change the activity of ChE. These changes can pertain an increase or decrease in enzyme activity; as there might be no change. The type of opioid used may have an effect on the cholinergic modulation. It is beneficial to conduct cross-sectional and cohort studies on addicted individuals, especially opium abusers, to find the precise association of opioids with alterations in human acetyl cholinesterase or butyrylcholinesterase. Simulation studies can also examine the structure-function relationships and provide important details to better understand the mechanism of action of opioid compounds on ChE activity. In addition, understanding how opioids impact ChE activity may help perform proper interventions for drug abstinence.

Addressing opioid tolerance and opioid-induced hypersensitivity: Recent developments and future therapeutic strategies.

Opioids are a commonly prescribed and efficacious medication for the treatment of chronic pain but major side effects such as addiction, respiratory depression, analgesic tolerance, and paradoxical pain hypersensitivity make them inadequate and unsafe for patients requiring long‐term pain management. This review summarizes recent advances in our understanding of the outcomes of chronic opioid administration to lay the foundation for the development of novel pharmacological strategies that attenuate opioid tolerance and hypersensitivity; the two main physiological mechanisms underlying the inadequacies of current therapeutic strategies. We also explore mechanistic similarities between the development of neuropathic pain states, opioid tolerance, and hypersensitivity which may explain opioids’ lack of efficacy in certain patients. The findings challenge the current direction of analgesic research in developing non‐opioid alternatives and we suggest that improving opioids, rather than replacing them, will be a fruitful avenue for future research.

Chronic Opioid Administration is Associated with Prevotella-dominated Dysbiosis in SIVmac251 Infected, cART-treated Macaques.

People living with the human immunodeficiency virus (HIV) have an elevated risk of opioid misuse due to both prescriptions for HIV-associated chronic pain and because injection drug use remains a primary mode of HIV transmission. HIV pathogenesis is characterized by chronic immune activation and microbial dysbiosis, and translocation across the gut barrier exacerbating inflammation. Despite the high rate of co-occurrence, little is known about themicrobiome during chronic opioid use in the context of HIV and combination antiretroviral therapy(cART). We recently demonstrated the reduction of the CD4 + T-cell reservoir in lymphoid tissues but increased in microglia/macrophage reservoirs in CNS by using morphine-treated, simian immunodeficiency virus (SIV)-infected rhesus macaques with viremia suppressed by cART. To understand whether morphine may perturb the gut-brain axis, fecal samples were collected at necropsy, DNA isolated, and 16S rRNA sequenced and changes of the microbiomeanalyzed. We found that morphine treatment led to dysbiosis, primarily characterized by expansion of Bacteroidetes, particularly Prevotellaceae, at the expense of Firmicutes and other members of healthy microbial communities resulting in a lower α-diversity. Of the many genera in Prevotellaceae, the differences between the saline and morphine group were primarily due to a higher relative abundance of Prevotella_9, the taxa most similar to Prevotella copri, an inflammatory pathobiont in the human microbiome. These findings reinforce previous research showing that opioid abuse is associated with dysbiosis, therefore, warranting additional future research to elucidate the complex interaction between the host and opioid abuse during HIV and SIV infection.

Kratom Alkaloids, Natural and Semi-Synthetic, Show Less Physical Dependence and Ameliorate Opioid Withdrawal.

Chronic administration of opioids produces physical dependence and opioid-induced hyperalgesia. Users claim the Thai traditional tea "kratom" and component alkaloid mitragynine ameliorate opioid withdrawal without increased sensitivity to pain. Testing these claims, we assessed the combined kratom alkaloid extract (KAE) and two individual alkaloids, mitragynine (MG) and the analog mitragynine pseudoindoxyl (MP), evaluating their ability to produce physical dependence and induce hyperalgesia after chronic administration, and as treatments for withdrawal in morphine-dependent subjects. C57BL/6J mice (n = 10/drug) were administered repeated saline, or graded, escalating doses of morphine (intraperitoneal; i.p.), kratom alkaloid extract (orally, p.o.), mitragynine (p.o.), or MP (subcutaneously, s.c.) for 5days. Mice treated chronically with morphine, KAE, or mitragynine demonstrated significant drug-induced hyperalgesia by day 5 in a 48 °C warm-water tail-withdrawal test. Mice were then administered naloxone (10 mg/kg, s.c.) and tested for opioid withdrawal signs. Kratom alkaloid extract and the two individual alkaloids demonstrated significantly fewer naloxone-precipitated withdrawal signs than morphine-treated mice. Additional C57BL/6J mice made physically dependent on morphine were then used to test the therapeutic potential of combined KAE, mitragynine, or MP given twice daily over the next 3days at either a fixed dose or in graded, tapering descending doses. When administered naloxone, mice treated with KAE, mitragynine, or MP under either regimen demonstrated significantly fewer signs of precipitated withdrawal than control mice that continued to receive morphine. In conclusion, while retaining some liabilities, kratom, mitragynine, and mitragynine pseudoindoxyl produced significantly less physical dependence and ameliorated precipitated withdrawal in morphine-dependent animals, suggesting some clinical value.

The cannabinoid CB2 receptor agonist LY2828360 synergizes with morphine to suppress neuropathic nociception and attenuates morphine reward and physical dependence

The opioid crisis has underscored the urgent need to identify safe and effective therapeutic strategies to overcome opioid-induced liabilities. We recently reported that LY2828360, a slowly signaling G protein-biased cannabinoid CB2 receptor agonist, suppresses neuropathic nociception and attenuates the development of tolerance to the opioid analgesic morphine in paclitaxel-treated mice. Whether beneficial effects of LY2828360 are dependent upon the presence of a pathological pain state are unknown and its impact on unwanted opioid-induced side-effects have never been investigated. Here, we asked whether LY2828360 would produce synergistic anti-allodynic effects with morphine in a paclitaxel model of chemotherapy-induced neuropathic pain and characterized its impact on opioid-induced reward and other unwanted side-effects associated with chronic opioid administration. Isobolographic analysis revealed that combinations of LY2828360 and morphine produced synergistic anti-allodynic effects in suppressing paclitaxel-induced mechanical allodynia. In wildtype (WT) mice, LY2828360 blocked morphine-induced reward in a conditioned place preference assay without producing reward or aversion when administered alone. The LY2828360-induced attenuation of morphine-induced reward was absent in CB2 knockout (CB2KO) mice. In the absence of a neuropathic pain state, LY2828360 partially attenuated naloxone-precipitated opioid withdrawal in morphine-dependent WT mice, and this withdrawal was itself markedly exacerbated in CB2KO mice. Moreover, LY2828360 did not reliably alter morphine-induced slowing of colonic transit or attenuate tolerance to morphine antinociceptive efficacy in the hot plate test of acute nociception. Our results suggest that cannabinoid CB2 receptor activation enhances the therapeutic properties of opioids while attenuating unwanted side-effects such as reward and dependence that occur with sustained opioid treatment.

Positive Allosteric Modulation of CB1 Cannabinoid Receptor Signaling Enhances Morphine Antinociception and Attenuates Morphine Tolerance Without Enhancing Morphine- Induced Dependence or Reward.

Opioid analgesics represent a critical treatment for chronic pain in the analgesic ladder of the World Health Organization. However, their use can result in a number of unwanted side-effects including incomplete efficacy, constipation, physical dependence, and overdose liability. Cannabinoids enhance the pain-relieving effects of opioids in preclinical studies and dampen unwanted side-effects resulting from excessive opioid intake. We recently reported that a CB1 positive allosteric modulator (PAM) exhibits antinociceptive efficacy in models of pathological pain and lacks the adverse side effects of direct CB1 receptor activation. In the present study, we evaluated whether a CB1 PAM would enhance morphine’s therapeutic efficacy in an animal model of chemotherapy-induced neuropathic pain and characterized its impact on unwanted side-effects associated with chronic opioid administration. In paclitaxel-treated mice, both the CB1 PAM GAT211 and the opioid analgesic morphine reduced paclitaxel-induced behavioral hypersensitivities to mechanical and cold stimulation in a dose-dependent manner. Isobolographic analysis revealed that combinations of GAT211 and morphine resulted in anti-allodynic synergism. In paclitaxel-treated mice, a sub-threshold dose of GAT211 prevented the development of tolerance to the anti-allodynic effects of morphine over 20 days of once daily dosing. However, GAT211 did not reliably alter somatic withdrawal signs (i.e., jumps, paw tremors) in morphine-dependent neuropathic mice challenged with naloxone. In otherwise naïve mice, GAT211 also prolonged antinociceptive efficacy of morphine in the tail-flick test and reduced the overall right-ward shift in the ED50 for morphine to produce antinociception in the tail-flick test, consistent with attenuation of morphine tolerance. Pretreatment with GAT211 did not alter somatic signs of μ opioid receptor dependence in mice rendered dependent upon morphine via subcutaneous implantation of a morphine pellet. Moreover, GAT211 did not reliably alter μ-opioid receptor-mediated reward as measured by conditioned place preference to morphine. Our results suggest that a CB1 PAM may be beneficial in enhancing and prolonging the therapeutic properties of opioids while potentially sparing unwanted side-effects (e.g., tolerance) that occur with repeated opioid treatment.

Continuous opioid administration in adult rats causes differential tolerance to develop in measures of respiratory, behavioral, and analgesic effects

Opioid drugs cause potent suppression of augmented breaths (ABs). Since many physiological effects of opioids demonstrate tolerance, in this study we sought to determine the temporal pattern and degree of any such tolerance in the suppression of ABs during 6 days of chronic opioid administration. Adult male rats (average 439.8 ± 19 g) received a continuous infusion of either saline (SAL, 0.01 ml/hr, n=5) or methadone (MET, 6 mg/kg/day, n=5) over 6 days via subcutaneously implanted osmotic pumps (Alzet, model 2ML1). Another control group received the cannabinoid receptor agonist WIN 55,212‐2 (WIN, 40 mg/kg/day, n=5), as a means of examining the potential confounding effect of altered behavioral activity on variables of interest. Animals were monitored before surgical implantation (D0), and again on days 2, 4 and 6 post‐implant (D2, D4, D6, respectively). Respiratory variables were measured using whole‐body plethysmography, pain tolerance assessed via tail flick latency (TF), and rearing behavior recorded as an index of behavioral alteration. All outcome variables of interest were analyzed using a mixed model ANOVA and appropriate post‐hoc comparisons, with monitoring day being the within‐animal factor and experimental group being the between‐animal factor considered. We found no differences in baseline measurements between experimental groups. During treatment, MET animals experienced a powerful suppression of ABs (D0 = 6.2 ± 0.383 ABs/15 min, vs. D2 = 1.4 ± 0.447, p<0.001), with tolerance developing across D4 and D6 (3.0 ± 0.523, p<0.001 and 5.0 ± 0.469, p=0.083 vs D0, respectively). No suppression of ABs was observed in either SAL or WIN animals across D0‐D6. Rearing behavior was suppressed in MET (P<0.001 for D2‐D6 vs. D0) and WIN animals across D2‐D6 (P<0.001 for D2‐D6 vs. D0), but not in SAL. However, MET animals demonstrated tolerance in rearing behavior over the 6 days of treatment, increasing back towards baseline on D6 vs. D2, P<0.001). In contrast, WIN animal rearing behavior continued to decrease across D2‐D6 vs baseline. TF latency was prolonged in MET (D0 = 2.812± 0.246 s vs 11.520± 0.389 s, 10.796± 0.152 s, & 10.739± 0.281 s on D2, D4, D6 respectively, all p<0.001), and no significant tolerance was observed across 6 days of treatment in MET animals. TF latency was prolonged in WIN only on D2 vs D0 (6.162± 0.389 s vs 3.826± 0.246, P= 0.002) to a lesser degree than in the MET animals, with no effect observed in SAL animals (p<0.001). We conclude that continuous opioid administration causes profound suppression of ABs with significant tolerance developing towards 6 days of treatment. This tolerance has a temporal pattern dissociated from behavioral effects, and markedly dissimilar to that of the analgesic effect. WIN does not cause any significant alteration of AB production despite a progressively profound suppression of behavioral activity. We propose that the mechanisms of suppression of ABs during opioid treatment follows an opioid‐receptor‐mediated pathway that is distinct from those mediating either analgesic or behavioral effects. It is therefore promising that targeted adjunct therapies to prevent the suppression of ABs during opioid treatment may be developed, that spare therapeutically desirable analgesic effects.

Interruption of continuous opioid exposure exacerbates drug-evoked adaptations in the mesolimbic dopamine system.

Drug-evoked adaptations in the mesolimbic dopamine system are postulated to drive opioid abuse and addiction. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. We exposed male and female mice to morphine for one week, with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with either naloxone-precipitated or spontaneous withdrawal. Continuous morphine exposure caused tolerance to the psychomotor-activating effects of morphine, whereas both intermittent and interrupted morphine exposure caused long-lasting psychomotor sensitization. Given links between locomotor sensitization and mesolimbic dopamine signaling, we used fiber photometry and a genetically encoded dopamine sensor to conduct longitudinal measurements of dopamine dynamics in the nucleus accumbens. Locomotor sensitization caused by interrupted morphine exposure was accompanied by enhanced dopamine signaling in the nucleus accumbens. To further assess downstream consequences on striatal gene expression, we used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in both nucleus accumbens and dorsal striatum, dramatically increasing differential gene expression and engaging unique signaling pathways. Our study indicates that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may, therefore, represent a strategy to minimize iatrogenic effects on brain reward circuits.

Carbonyl-protein content increases in brain and blood of female rats after chronic oxycodone treatment

BackgroundOpioids are the most effective drugs commonly prescribed to treat pain. Due to their addictive nature, opioid pain relievers are now second to marijuana, ahead of cocaine with respect to dependence. Ours and other studies suggest potential toxic effects of chronic opioid administration leading to neuronal degeneration. It has been suggested that protein carbonylation may represent a sensitive biomarker of cellular degeneration. To evaluate whether prolonged oxycodone administration is associated with accumulation of protein aggregates that may contribute to neuronal degeneration we measured protein carbonylation levels in brain and also in blood plasma of rats after 30-days of 15 mg/kg daily oxycodone administration.ResultsWe observed a significant increase in the level of carbonylated proteins in rat brain cortex after 30-days of oxycodone treatment compare to that in water treated animals. Also, oxycodone treated rats demonstrated accumulation of insoluble carbonyl-protein aggregates in blood plasma.ConclusionsOur data suggests that tests detecting insoluble carbonyl-protein aggregates in blood may serve as an inexpensive and minimally invasive method to monitor neuronal degeneration in patients with a history of chronic opioid use. Such methods could be used to detect toxic side effects of other medications and monitor progression of aging and neurodegenerative diseases.

Effects of Separate and Combined Chronic Ingestion of Codeine and Tramadol on Self Grooming Behavior of Male and Female Albino Rats

Rodent self-grooming comprises behaviors devoted to caring of the body surface; presentations that have apparent stereotyped and recurring characteristics which makes rodent grooming a appropriate translational tool for studying the effects of substance abuse in humans. Two opioids, codeine and tramadol, both used for the relief of mild to moderately severe pain but overtime has been abused by people to relieve emotional pain were considered in this study. 54 male and female albino rats (24 females and 30 males) with weight ranging from 120g-180g rats were assigned to three experimental groups (codeine, tramadol and combined group) and one control group. In the study, 6 rats were assigned per group. Rats in the codeine group were orally administered 8mg/kg of codeine while rats in the tramadol group were administered with 20mg/kg of tramadol. Rats in the combined group were administered both 8mg/kg of codeine and 10mg/kg of tramadol. Female rats exposed to chronic intake of Tramadol only (Mean =3.14) were found to significantly displayed more body licking grooming behavior compared to female rats administered Codeine only (Mean = 1.33), combination of Codeine and Tramadol (mean = .67) and the control (mean =1.79) (<i>p</i> < .001). Whereas, male rats in the control (mean = 4.23) significantly displayed more body licking grooming behavior compared to male rats administered Codeine only (mean = 3.01), Tramadol only (mean = 3.35), and the combination of Codeine and Tramadol (mean = 2.49) (<i>p</i> < .05). Also, female rats exposed to chronic intake of Codeine only (mean = 4.92), significantly displayed more daily face washing grooming behavior compared to female rats administered Tramadol only (mean = 3.33), combination of Codeine and Tramadol (mean = 3.29) and the control group (mean = 4.76) (<i>p</i> < .001). Whereas, male rats exposed to chronic intake of Codeine only (mean = 4.92), significantly displayed more daily face washing grooming behavior compared to male rats administered Tramadol only (mean = 3.33), combination of Codeine and Tramadol (mean = 3.29) and the control group (mean = 4.76) (<i>p</i> < .001). The findings demonstrated that chronic administration of opioids, codeine and tramadol affected grooming behaviors i.e. face washing and body licking behaviors which are related to possible deterioration of physical appearance and personal grooming habits in humans. Hence, the study suggests that further exploration to unravel the risks related to the consistent consumption of codeine and tramadol on other body systems be considered.

Chronic opioid administration results in μ-opioid receptor excitatory signaling at a descending pain facilitatory area of the brain

Chronic opioid administration results in μ-opioid receptor excitatory signaling at a descending pain facilitatory area of the brain