Opioid Addiction Research Articles

An emerging multi-omic understanding of the genetics of opioid addiction.

Opioid misuse, addiction, and associated overdose deaths remain global public health crises. Despite the tremendous need for pharmacological treatments, current options are limited in number, use, and effectiveness. Fundamental leaps forward in our understanding of the biology driving opioid addiction are needed to guide development of more effective medication-assisted therapies. This Review focuses on the omics-identified biological features associated with opioid addiction. Recent GWAS have begun to identify robust genetic associations, including variants in OPRM1, FURIN, and the gene cluster SCAI/PPP6C/RABEPK. An increasing number of omics studies of postmortem human brain tissue examining biological features (e.g., histone modification and gene expression) across different brain regions have identified broad gene dysregulation associated with overdose death among opioid misusers. Drawn together by meta-analysis and multi-omic systems biology, and informed by model organism studies, key biological pathways enriched for opioid addiction-associated genes are emerging, which include specific receptors (e.g., GABAB receptors, GPCR, and Trk) linked to signaling pathways (e.g., Trk, ERK/MAPK, orexin) that are associated with synaptic plasticity and neuronal signaling. Studies leveraging the agnostic discovery power of omics and placing it within the context of functional neurobiology will propel us toward much-needed, field-changing breakthroughs, including identification of actionable targets for drug development to treat this devastating brain disease.

Specific receptor drugs in the therapeutic strategy of opioid addiction

Not available.

Playful Resilience: Empowering Recovery through Autobiographical Game-Based Storytelling in the Opioid Epidemic

The opioid epidemic is a persistent public health problem throughout Canada, with opioid-related deaths spiking during the COVID-19 pandemic. Focusing on Brantford and Hamilton, Ontario, which have high rates of opioid poisoning, this participatory game jam project examines how 21 adults (ages 18+) with a history of opioid addiction make sense of their life experiences through the processes of autobiographical game-based storytelling, including ideation, narrative design, and environmental storytelling. Phenomenological interviews, processual artifacts like concept sketches, doodles, and reflections, and game prototypes generated through Scratch, Twine, and Bitsy facilitated the exploration of six key phenomena representing autobiographical game-based storytelling: maze metaphors, decision-making, compact games, morality and religion, resilience, and social communion. This interdisciplinary project explores how game-based storytelling supports recovery and restores dignity among adults experiencing opioid addiction while raising awareness of health inequities, thereby humanizing the opioid crisis.

Genetic Associations of Persistent Opioid Use After Surgery Point to OPRM1 but Not Other Opioid-Related Loci as the Main Driver of Opioid Use Disorder.

Persistent opioid use after surgery is a common morbidity outcome associated with subsequent opioid use disorder, overdose, and death. While phenotypic associations have been described, genetic associations remain unidentified. Here, we conducted the largest genetic study of persistent opioid use after surgery, comprising ~40,000 non-Hispanic, European-ancestry Michigan Genomics Initiative participants (3198 cases and 36,321 surgically exposed controls). Our study primarily focused on the reproducibility and reliability of 72 genetic studies of opioid use disorder phenotypes. Nominal associations (p < 0.05) occurred at 12 of 80 unique (r2 < 0.8) signals from these studies. Six occurred in OPRM1 (most significant: rs79704991-T, OR = 1.17, p = 8.7 × 10-5), with two surviving multiple testing correction. Other associations were rs640561-LRRIQ3 (p = 0.015), rs4680-COMT (p = 0.016), rs9478495 (p = 0.017, intergenic), rs10886472-GRK5 (p = 0.028), rs9291211-SLC30A9/BEND4 (p = 0.043), and rs112068658-KCNN1 (p = 0.048). Two highly referenced genes, OPRD1 and DRD2/ANKK1, had no signals in MGI. Associations at previously identified OPRM1 variants suggest common biology between persistent opioid use and opioid use disorder, further demonstrating connections between opioid dependence and addiction phenotypes. Lack of significant associations at other variants challenges previous studies' reliability.

Orbitofrontal cortex to dorsal striatum circuit is critical for incubation of oxycodone craving after forced abstinence.

Relapse is a major challenge in treating opioid addiction, including oxycodone. During abstinence, oxycodone seeking progressively increases, a phenomenon termed incubation of oxycodone craving. We previously demonstrated a causal role of orbitofrontal cortex (OFC) in this incubation. Here, we studied the interaction between glutamatergic projections from OFC and dopamine 1-family receptor (D1R) signaling in dorsal striatum (DS) in this incubation in male rats. We first examined the causal role of D1R signalling in DS in incubated oxycodone seeking. Next, we combined fluorescence-conjugated cholera toxin subunit B (CTb-555, a retrograde tracer) with Fos (a neuronal activity marker) to assess whether the activation of OFC→DS projections was associated with incubated oxycodone seeking. We then used a pharmacological asymmetrical disconnection procedure to examine the role of the interaction between projections from OFC and D1R signalling in DS in incubated oxycodone seeking. We also tested the effect of unilateral pharmacological inactivation of OFC or unilateral D1R blockade of DS on incubated oxycodone seeking. Finally, we assessed whether contralateral disconnection of OFC→DS projections impacted non-incubated oxycodone seeking on abstinence day 1. We found that D1R blockade in DS decreased incubated oxycodone seeking and OFC→DS projections were activated during incubated oxycodone seeking. Moreover, anatomical disconnection of OFC→DS projections, but not unilateral inactivation of OFC or unilateral D1R blockade in DS, decreased incubated oxycodone seeking. Lastly, contralateral disconnection of OFC→DS projections had no effect on oxycodone seeking on abstinence day 1. Together, these results demonstrated a causal role of OFC→DS projections in incubation of oxycodone craving.

Filling the Treatment Gap: Geographic Expansion of Buprenorphine Providers Across the U.S.

ObjectiveWith opioid-related deaths reaching epidemic levels, gaining a better understanding of access to treatment for opioid use disorder (OUD) is critical. Buprenorphine is an effective medication for the treatment of opioid addiction. The analysis is critical post-X-waiver elimination which extended the ability to prescribe buprenorphine for the treatment of OUD to all practitioners with DEA Schedules II-V on their DEA Registration. The primary purpose of the analysis was to explore the geographic patterns of substance use treatment and establish a geographical baseline to assess the removal of the X-Waiver in the future. Data and MethodsWe assessed the expansion of buprenorphine providers across the data from all US counties up to December 31, 2022. We used all certified buprenorphine providers' data from the database of the buprenorphine waiver notification system (BWNS). We used county-level population data from the US Census of American Community Survey (ACS) of 2021 and the CDC's Drug-related mortality data. We implemented spatial scan statistics to identify the spatial clusters using SaTScan. ResultsThe results from our analysis show that Doctor of Medicine/Doctor of Osteopathic Medicine (MD/DO) have the highest numbers of certified providers at 8134 (65.08%) in 2018 and 14525 (57.87%) in 2022. Our analysis shows that the distribution of buprenorphine providers across the counties of the United States was significantly clustered. Higher clusters with RR of more than 1 (p-value <0.001) were found in the states of Washington, Oregon, Northern California, and the Western borders of Montana. Similar clusters of counties with RR more than 1 (p-value <0.001) were found in the northeastern states of Maine, Vermont, and New Hampshire. ConclusionsFrom our analysis, it is evident that buprenorphine-certified providers are clustered in areas of higher drug-related mortality filling a treatment gap. The elimination of the X-waiver will be a significant step towards increasing access to MOUD and this analysis may be used as a geographical baseline to assess in the future.

The Gut-Brain Axis in Opioid Use Disorder: Exploring the Bidirectional Influence of Opioids and the Gut Microbiome-A Comprehensive Review.

Opioid Use Disorder is a chronic condition characterized by compulsive opioid use despite negative consequences, resulting in severe health risks such as overdose and contraction of infectious diseases. High dropout rates in opioid agonist therapy highlight the need for more effective relapse prevention strategies. Animal and clinical studies indicate that opioids influence gut microbiota, which in turn plays a critical role in addiction development and alters behavioral responses to opioids. This study provides a comprehensive review of the literature on the effects of opioids on the gut microbiome and explores the potential of microbiome manipulation as a therapeutic target in opioid addiction.

Conotoxins: emerging analgesics for neck and spinal surgery pain management

Conotoxins, peptides derived from the venom of marine cone snails, have emerged as promising analgesics for managing pain associated with neck and spinal surgery. These toxins target specific neurotransmitter receptors and ion channels in the nervous system, offering an alternative to traditional opioids with potentially fewer side effects. By interacting with receptors such as nicotinic acetylcholine and voltage-gated sodium and calcium channels, conotoxins disrupt pain signal transmission and induce muscle relaxation, providing effective pain relief. Research into conotoxins is ongoing, with the goal of developing novel, safer analgesics that mitigate the risks of opioid addiction. This exploration not only holds promise for surgical pain management but also advances our understanding of venom pharmacology and its therapeutic applications.

Sex-specific Concordance of Striatal Transcriptional Signatures of Opioid Addiction in Human and Rodent Brains.

Opioid use disorder (OUD) has emerged as a severe, ongoing public health emergency. Current, frontline addiction treatment strategies fail to produce lasting abstinence in most users. This underscores the lasting effects of chronic opioid exposure and emphasizes the need to understand the molecular mechanisms of drug seeking and taking, but also how those alterations persist through acute and protracted withdrawal. Here, we used RNA sequencing in post-mortem human tissue from males (n=10) and females (n=10) with OUD and age and sex-matched comparison subjects. We compared molecular alterations in the nucleus accumbens (NAc) and dorsolateral prefrontal cortex (DLPFC) between humans with OUD and rodent models across distinct stages of opioid use and withdrawal (acute and prolonged) using differential gene expression and network-based approaches. We found that the molecular signature in the NAc of females with OUD mirrored effects seen in the NAc of female mice at all stages of exposure. Conversely, males with OUD showed strong overlap in expression profile with rats in acute withdrawal. Co-expression networks involved in post-transcriptional modification of RNA and epigenetic modification of chromatin state. This study provides fundamental insight into the converging molecular pathways altered by opioids across species. Further, this work helps to disentangle which alterations observed in humans with OUD are driven by acute drug exposure and which alterations are consequences of chronic exposure.

YTHDF1 in periaqueductal gray inhibitory neurons contributes to morphine withdrawal responses in mice

BackgroundPhysical symptoms and aversion induced by opioid withdrawal strongly affect the management of opioid addiction. YTH N6-methyladenosine (m6A) RNA binding protein 1 (YTHDF1), an m6A-binding protein, from the periaqueductal gray (PAG) reportedly contributes to morphine tolerance and hyperalgesia. However, the role of YTHDF1 in morphine withdrawal remains unclear.MethodsA naloxone-precipitated morphine withdrawal model was established in C57/BL6 mice or transgenic mice. YTHDF1 was knocked down via adeno-associated virus transfection. Combined with the results of the single-cell RNA sequencing analysis, the changes in morphine withdrawal somatic signs and conditioned place aversion (CPA) scores were compared when YTHDF1 originating from different neurons in the ventrolateral periaqueductal gray (vlPAG) was knocked down. We further explored the role of inflammatory factors and transcription factors related to inflammatory response in morphine withdrawal.ResultsOur results revealed that YTHDF1 expression was upregulated in the vlPAG of mice with morphine withdrawal and that the knockdown of vlPAG YTHDF1 attenuated morphine withdrawal-related somatic signs and aversion. The levels of NF-κB and p-NF-κB were reduced after the inhibition of YTHDF1 in the vlPAG. YTHDF1 from vlPAG inhibitory neurons, rather than excitatory neurons, facilitated morphine withdrawal responses. The inhibition of YTHDF1 in vlPAG somatostatin (Sst)-expressing neurons relieved somatic signs of morphine withdrawal and aversion, whereas the knockdown of YTHDF1 in cholecystokinin (Cck)-expressing or parvalbumin (PV)-expressing neurons did not change morphine withdrawal-induced responses. The activity of c-fos + neurons, the intensity of the calcium signal, the density of dendritic spines, and the frequency of mIPSCs in the vlPAG, which were increased in mice with morphine withdrawal, were decreased with the inhibition of YTHDF1 from vlPAG inhibitory neurons or Sst-expressing neurons. Knockdown of NF-κB in Sst-expressing neurons also alleviated morphine withdrawal-induced responses.ConclusionsYTHDF1 originating from Sst-expressing neurons in the vlPAG is crucial for the modulation of morphine withdrawal responses, and the underlying mechanism might be related to the regulation of the expression and phosphorylation of NF-κB.

Opioid drug seeking after early-life adversity: a role for delta opioid receptors

Opioid use disorder (OUD) is associated with a history of early-life adversity (ELA), an association that is particularly strong in women. In a rodent model, we previously found that ELA enhances risk for opioid addiction selectively in females, but the mechanisms for this effect are unclear. Here, we show that ELA robustly alters cFos responses to opioid drugs in females’ nucleus accumbens (NAc) and basolateral amygdala (BLA), but not elsewhere. We further identify delta opioid receptors (DOR), which mature in the first week of life and thus later than kappa or mu opioid receptors, as a potential mediator of ELA's impacts on reward circuit functions. Accordingly, DOR mRNA in NAc was persistently reduced in adult females with ELA history. Moreover, pharmacological stimulation of NAc DORs increased opioid demand in control females (recapitulating the ELA phenotype), while blocking DORs in ELA females conversely reduced high-effort drug consumption, simulating the control rearing phenotype. These findings support a role for NAc DORs in mediating ELA-induced opioid vulnerability. In contrast, BLA neurons expressing DOR protein do not overlap heroin- responsive cells in ELA rats, arguing against a direct relationship of BLA DORs to heroin's addiction-relevant actions in the brain. Together, these results suggest a novel and selective role for NAc DORs in contributing to enduring, ELA-provoked vulnerability to OUD.

Retrospective analysis of opioid use in patients with and without cryoneurolysis prior to total knee arthroplasty: a comparison cohort study

Introduction Routine usage of opioids to manage pain in the post-operative period is commonplace following many orthopaedic procedures. As the trends of opioid abuse and addiction have been primarily linked to an increase in opioid prescriptions, more attention has been focused on reducing opioid prescriptions by managing postoperative pain via alternative methods. The objective of this study was to determine if cryoneurolysis within three months prior to total knee arthroplasty (TKA) resulted in reduced opioid consumption postoperatively. Materials and Methods An IRB approved retrospective review of 183 patients who underwent primary TKA between August 2022 and February 2023 was conducted. The primary outcome was postoperative opioid usage was compared between patients who received cryoneurolysis within three months prior to TKA compared with patients who did not receive cryoneurolysis preoperatively. Secondary outcomes included postoperative knee range of motion (ROM) and referral to physical therapy. Results No statistically significant difference was observed in postoperative opioid consumption for patients who underwent cryoneurolysis prior to TKA compared with patients who did not undergo cryoneurolysis prior to surgery. Discussion Although cryoneurolysis within three months prior to TKA failed to produce a statistically significant decrease in postoperative opioid consumption, the lead author’s preoperative treatment pathway did result in overall reduction in opioid consumption compared to previously published studies. Conclusion The results of this study suggest that cryoneurolysis within three months prior to TKA does not reduce patient postoperative opioid consumption.

Syndemic Connections: Overdose Death Crisis, Gender-Based Violence and COVID-19

This article will use syndemic theory to identify and analyze overlapping health and social conditions, focusing specifically on how gender-based violence is systemically interconnected with contemporary public health issues. The overdose death crisis that continues to afflict Canadian populations is not an isolated health issue. Across Canada, it is intertwined with mental health, HIV/AIDS, COVID-19 and structural violence—the chronic and systemic disadvantages affecting those living in poverty and oppressive circumstances. Opioid use is an often-avoidant coping strategy for many experiencing the effects of trauma, relentless fear, pain, ill health and social exclusion. In particular, Indigenous and non-Indigenous women’s experiences with opioid addiction are entangled with encounters with gender based-violence, poverty and chronic ailments within structurally imposed processes and stressors shaped by a history of colonialism, ruptured lifeways and Western ways of knowing and doing, leading to disproportionate harms and occurrences of illness. While biomedical models of comorbidity and mortality approach substance misuse, gender-based violence and major infectious diseases such as HIV/AIDS and COVID-19 as distinct yet compounding realities, this article argues that these conditions are synergistically interrelated via the critical/reflexive lens of syndemic frameworks. Through secondary research using academic, media and policy sources from the past decade in Canada, complemented by prior ethnographic research, the synergistic connections among opioid addiction, gender-based violence and the effects of the COVID pandemic on diverse women will be shown to be driven by socio-structural determinants of health including poverty, intergenerational trauma, the legacy of colonialism and Western optics. Together, they embody a contemporary Canadian syndemic necessitating coordinated responses.

Morphine-like Novel Compounds for the Treatment of Depressive Symptoms

: Depression is a severe mental disorder characterized by a major imbalance between the levels of neurotransmitters. US11534436 B2 discloses an efficient amount of µ-opioid receptor agonists or their pharmaceutically acceptable salt for efficient treatment of depression. The patent discloses a few new compounds among which compounds 1, 2, 3, 4, and 5 as well as derivatives of basic nucleus A have good µ-opioid receptor agonist activity without risks of opioid addiction or development of addiction withdrawal symptoms. The compounds displayed Emax of 5% to 45% in a GTPγS binding assay while one of the derivatives displayed Emax of 15% to 35% in a GTPγS binding assay. The patent further discloses different embodiments with different potentials. The administration of an effective dose in rats resulted in 125% to 300% efflux of dopamine of baseline. At a dosage of 1-10 mg/kg, the embodiments do not diminish the thermal pain in rodents. Although the patent explored new µ-opioid receptor agonists for the treatment of depressive symptoms, the exhaustive evaluation of toxicity and further mechanisms need to be explored via in vivo models.

Comparative Analysis of LORETA Z Score Neurofeedback and Cognitive Rehabilitation on Quality of Life and Response Inhibition in Individuals with Opioid Addiction.

Background. Previous studies has shown that conventional neurofeedback and cognitive rehabilitation can improve psychological outcomes in people with opioid use disorders. However, the effectiveness of LORETA Z-score neurofeedback (LZNFB) and attention bias modification training on quality of life and inhibitory control of these people has not been investigated yet. LZNFB targets deeper brain structures with higher precision, compared to conventional neurofeedback that typically focuses on surface EEG activity. The present study aims to compare the effect of these two methods on quality of life and response inhibition in men with opioid use disorders under methadone maintenance therapy (MMT). Methods. In this randomized controlled clinical trial with a pre-test, post-test, follow-up design, 30 men with opioid use disorders under MMT were randomly assigned into three groups of LZNFB, attention bias modification training, and control (MMT alone). The LZNFB and Cognitive Rehabilitation groups received 20 and 15 sessions of treatment, respectively. The Persian versions WHO Quality of Life-BREEF questionnaire and the Go/No-Go test were completed by the participants before, immediately after, and one month after interventions. The collected data were analyzed in SPSS v.22 software. Results. Both intervention groups showed a significant improvement in quality-of-life score and a significant reduction in response time at the post-test phase (P < .05), where LZNFB group showed more improvement in quality of life and more reduction in response inhibition. After one month, the increase in quality of life continued in both groups, while the decrease in response time continued only in the LZNFB group. Conclusion. Both LZNFB and attention bias modification training are effective in improving quality of life and response inhibition of men with OUD under MMT, however, LZNFB is more effective.

Elucidating the molecular symphony: unweaving the transcriptional & epigenetic pathways underlying neuroplasticity in opioid dependence and withdrawal.

The persistent use of opioids leads to profound changes in neuroplasticity of the brain, contributing to the emergence and persistence of addiction. However, chronic opioid use disrupts the delicate balance of the reward system in the brain, leading to neuroadaptations that underlie addiction. Chronic cocaine usage leads to synchronized alterations in gene expression, causing modifications in the Nucleus Accumbens (NAc), a vital part of the reward system of the brain. These modifications assist in the development of maladaptive behaviors that resemble addiction. Neuroplasticity in the context of addiction involves changes in synaptic connectivity, neuronal morphology, and molecular signaling pathways. Drug-evoked neuroplasticity in opioid addiction and withdrawal represents a complicated interaction between environmental, genetic, and epigenetic factors. Identifying specific transcriptional and epigenetic targets that can be modulated to restore normal neuroplasticity without disrupting essential physiological processes is a critical consideration. The discussion in this article focuses on the transcriptional aspects of drug-evoked neuroplasticity, emphasizing the role of key transcription factors, including cAMP response element-binding protein (CREB), ΔFosB, NF-kB, Myocyte-enhancing factor 2 (MEF2), Methyl-CpG binding protein 2 (MeCP2), E2F3a, and FOXO3a. These factors regulate gene expression and lead to the neuroadaptive changes observed in addiction and withdrawal. Epigenetic regulation, which involves modifying gene accessibility by controlling these structures, has been identified as a critical component of addiction development. By unraveling these complex molecular processes, this study provides valuable insights that may pave the way for future therapeutic interventions targeting the mechanisms underlying addiction and withdrawal.

An Indigenous-led buprenorphine-naloxone treatment program to address opioid use in remote Northern Canada

Background/purposeIn response to the opioid use challenges exacerbated from the COVID-19 pandemic, Fort Albany First Nation (FAFN), a remote Cree First Nation community situated in subarctic Ontario, Canada, implemented a buprenorphine-naloxone program. The newly initiated program was collaboratively developed by First Nations' nurses and community leaders, driven by the community's strengths, resilience, and forward-thinking approach. Using the First Nations Information Governance Centre strengths-based model, this article examines discussions with four community leaders to identify key strengths and challenges that emerged during the implementation of this program. Methodsthis qualitative study amplify the positive aspects and community strengths through the power of oral narratives. We conducted 20 semi-structured face-to-face interviews with community members who helped lead FAFN's COVID-19 pandemic response. Utilizing the Medicine Wheel framework, this work introduces a holistic model for the buprenorphine-naloxone program that addresses the cognitive, physical, spiritual, and emotional dimensions of well-being. ResultsRecommendations to support this initiative included the need for culturally competent staff, customized education programs, and the expanding of the program. Additionally, there is a pressing need for increased funding to support these initiatives effectively and sustainably. The development of this program, despite challenges, underscores the vital role of community leadership and cultural sensitivity to address the opioid crisis in a positive and culturally safe manner. ConclusionThe study highlights the successes of the buprenorphine-naloxone program, which was developed in response to the needs arising from the pandemic, specifically addressing community members suffering from opioid addiction. The timely funding for this program came as the urgent needs of community members became apparent due to pandemic lockdowns and isolation. Holistic care, including mental health services and fostering community relations, is important. By centering conversations on community strengths and advocating for culturally sensitive mental health strategies that nurture well-being, resilience, and empowerment, these findings can be adapted and expanded to support other Indigenous communities contending with opioid addiction.

Roadblocks for Successful Treatment in Opioid Substitution Therapy Center in India: An Opinion based on Observation

In India, opioid addiction is a serious emerging problem. Opioid substitution therapy (OST), particularly buprenorphine, has been shown to be very cost-effective and has significant evidence of reduced drug-related HIV risk behaviors, crime, and illegal opioid usage. Raising the standard of living and enhancing public health is one of the main goals of this therapy, with a special emphasis on the center’s efforts to promote harm reduction. However, incidents of reported patient abuse or misuse of these drugs frequently lead to unfavourable opinions of this crucial life-saving procedure. Therefore, the administration and government must move immediately to address the issue.

Affective neuroscience personality traits in opioid use disorder patients: The relationship with earlier onset of substance use, the severity of addiction, and motivational factors to quit opiate use.

This study aims to explore the relationship between affective personality traits and opioid use disorder (OUD), including factors such as motivation to quit, addiction severity, and age of onset of drug use. This study included 141 patients with opioid addiction (OAP) and 160 age- and sex-matched healthy controls (HC). OAP were interviewed and diagnosed according to DSM-5 criteria. HC were screened for past or current drug use. Participants completed sociodemographic forms and the Affective Neuroscience Personality Scale (ANPS), and the OAP group also completed the Addiction Profile Index (API). SEEK, PLAY, and SADNESS were identified as different affective personality traits between OAP and HC groups. Addiction severity was positively correlated with SADNESS and ANGER, while the age of onset of drug use was correlated with ANGER. Risk factors for OA include family history of substance abuse, low education, and low PLAY scores, whereas risk factors for earlier substance use onset are childhood trauma and high ANGER scores. This study highlights the importance of understanding affective personality traits in OUD. These findings may deepen our understanding of the underlying mechanisms of OUD. The identification of these affective systems may have implications for the development of personalized prevention and treatment strategies.

Opioid-environment interaction: Contrasting effects of morphine administered in a novel versus familiar environment on acute and repeated morphine induced behavioral effects and on acute morphine ERK activation in reward associated brain areas

We report that environmental context can have a major impact on morphine locomotor behavior and ERK effects. We manipulated environmental context in terms of an environmental novelty/ familiarity dimension and measured morphine behavioral effects in both acute and chronic morphine treatment protocols. Wistar rats (n=7 per group) were injected with morphine 10 mg/kg or vehicle (s.c.), and immediately placed into an arena for 5 min, and locomotor activity was measured after one or 5 days. The morphine treatments were initiated either when the environment was novel or began after the rats had been familiarized with the arena by being given 5 daily nondrug tests in the arena. The results showed that acute and chronic morphine effects were strongly modified by whether the environment was novel or familiar. Acute morphine administered in a novel environment increased ERK activity more substantially in several brain areas, particularly in reward-associated areas such as the VTA in comparison to when morphine was given in a familiar environment. Repeated morphine treatments initiated in a novel environment induced a strong locomotor sensitization, whereas repeated morphine treatments initiated in a familiar environment did not induce a locomotor stimulant effect but rather a drug discriminative stimulus dis-habituation effect. The marked differential effects of environmental novelty/familiarity and ongoing dopamine activity on acute and chronic morphine treatments may be of potential clinical relevance for opioid drug addiction.