Release Of Endogenous Opioids Research Articles

Characterizing the opioidergic mechanisms of repetitive transcranial magnetic stimulation-induced analgesia: a randomized controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) is a promising technology to reduce chronic pain. Investigating the mechanisms of rTMS analgesia holds the potential to improve treatment efficacy. Using a double-blind and placebo-controlled design at both stimulation and pharmacologic ends, this study investigated the opioidergic mechanisms of rTMS analgesia by abolishing and recovering analgesia in 2 separate stages across brain regions and TMS doses. A group of 45 healthy participants were equally randomized to the primary motor cortex (M1), the dorsolateral prefrontal cortex (DLPFC), and the Sham group. In each session, participants received an intravenous infusion of naloxone or saline before the first rTMS session. Participants then received a second dose of rTMS session after the drugs were metabolized at 90 minutes. M1-rTMS-induced analgesia was abolished by naloxone compared with saline and was recovered by the second rTMS run when naloxone was metabolized. In the DLPFC, double but not the first TMS session induced significant pain reduction in the saline condition, resulting in less pain compared with the naloxone condition. In addition, TMS over the M1 or DLPFC selectively increased plasma concentrations of β-endorphin or encephalin, respectively. Overall, we present causal evidence that opioidergic mechanisms are involved in both M1-induced and DLPFC-rTMS-induced analgesia; however, these are shaped by rTMS dosage and the release of different endogenous opioids.

Opioidergic signaling contributes to food-mediated suppression of AgRP neurons

Opioids are generally known to promote hedonic food consumption. Although much of the existing evidence is primarily based on studies of the mesolimbic pathway, endogenous opioids and their receptors are widely expressed in hypothalamic appetite circuits as well; however, their role in homeostatic feeding remains unclear. Using a fluorescent opioid sensor, deltaLight, here we report that mediobasal hypothalamic opioid levels increase by feeding, which directly and indirectly inhibits agouti-related protein (AgRP)-expressing neurons through the μ-opioid receptor (MOR). AgRP-specific MOR expression increases by energy surfeit and contributes to opioid-induced suppression of appetite. Conversely, its antagonists diminish suppression of AgRP neuron activity by food and satiety hormones. Mice with AgRP neuron-specific ablation of MOR expression have increased fat preference without increased motivation. These results suggest that post-ingestion release of endogenous opioids contributes to AgRP neuron inhibition to shape food choice through MOR signaling.

Wet cupping induces endogenous opioid release in rats, a pilot study

Wet cupping induces endogenous opioid release in rats, a pilot study

Endogenous Opioid Release After Orgasm in Man: A Combined PET/Functional MRI Study.

The endogenous μ-opioid receptor (MOR) system plays a key role in the mammalian reward circuit. Human and animal experiments suggest the involvement of MORs in human sexual pleasure, yet this hypothesis currently lacks invivo support. Methods: We used PET with the radioligand [11C]carfentanil, which has high affinity for MORs, to quantify endogenous opioid release after orgasm in man. Participants were scanned once immediately after orgasm and once in a baseline state. Hemodynamic activity was measured with functional MRI during penile stimulation. Results: The PET data revealed significant opioid release in the hippocampus. Hemodynamic activity in the somatosensory and motor cortices and in the hippocampus and thalamus increased during penile stimulation, and thalamic activation was linearly dependent on self-reported sexual arousal. Conclusion: Our data show that endogenous opioidergic activation in the medial temporal lobe is centrally involved in sexual arousal, and this circuit may be implicated in orgasmic disorders.

H23 Traditional healing by skin cauterization (kaiy)

Abstract The practice of kaiy is an ancient medical traditional therapy that is still used in Africa and the Middle East. Kaiy is the Arabic word for cautery; a red-hot iron or coal is placed to the skin. This causes sharp circular, oval or linear burns that are placed in a symmetrical configuration, usually resulting in permanent scars. This practice is undertaken by traditional healers. A Somali woman was referred by her general practitioner to dermatology for an itchy scar on her mid-upper abdomen. She reported that 40 years ago, she had traditional skin cautery therapy to the area for bone pain, which was later diagnosed as rheumatoid arthritis. On examination, she had a 4 × 0.7 cm keloid scar that was treated with a course of KenalogTM injections. This sparked an interest in understanding the practice of kaiy, and a literature review was performed. Cauterization results in the burning of tissue in order to close wounds or stop bleeding. The patient’s symptoms help to decide the location of cauterization. For example, if the presenting complaint is jaundice, the cautery is placed on the left hand. Other medical presentations that kaiy is used for include back pain, headache, depression, chest pain and exorcism. Is this practice useful or are patients being burned for no reason? Historically, it was felt that it was valuable in preventing infection; however, there is no scientific basis for this. The practice was believed to result in the destruction of pathogenic substances within the body due to the extreme heat. Patients who have undergone this therapy report that it gives them short-term relief of their symptoms; this is likely to be due to the release of endogenous opioids, allowing the body to stop the sensation of unremitting pain. Complications are commonly witnessed and consist of deep skin burns, deferred wound healing and secondary wound infections. More serious complications include septic shock, ulceration and viral transmission such as hepatitis B (Farid MK, El-Mansoury A. Kaiy (traditional cautery) in Benghazi, Libya: complications versus effectiveness. Panafr Med J 2015; 22:98; Budair F. Dermatoses due to Arabic cultural and traditional practices. Indian J Dermatol Venereol Leprosy 2019; 85:448–54). Kaiy should be included in the differential diagnosis of a patient presenting with multiple symmetrical scars. Some patients may not be forthcoming in admitting to the treatment if not specifically asked. This presentation aims to increase awareness in dermatologists of this practice.

The Endocannabinoid System a Turning Point in Optimizing Physiotherapy Procedures in Knee Osteoarthritis

Introduction: Knee Osteoarthritis (KOA) is characterized by wear, tear, and it's a slowly progressive loss of cartilage, that becomes finally disabling. KOA is one of the most analyzed diseases by many medical specialties such as rheumatology, orthopedics, rehabilitation medicine, and physiotherapy. Major symptoms of KOA such as pain, dysfunction, and chronic low-grade inflammation will decrease the quality of life and eventually lead to locomotor disability. Since there are no effective ways to limit KOA progression, involvement of the endocannabinoid system (ECS) may be a non-pharmacological therapeutic alternative in the management of this disease. This study debate aspects of ways to modulate the ECS in KOA, using physiotherapeutic (PT) means such as TENS electroanalgesia, LASER biostimulation, and physical exercises with analgesic effects. Materials and Methods: In the study, we included 82 sources, with the following keywords in the title: knee osteoarthritis, cannabidiol, endocannabinoid, inflammatory pain, analgesia, neuropathic pain, physiotherapy, electrotherapy, and LASER. To perform this review, we searched for the most relevant articles in the field of medicine and physiotherapy in 7 international databases applying inclusion and exclusion criteria. Results: The application of TENS currents in certain doses and frequencies together with LASER biostimulation stimulates the production of endocannabinoids thus controlling pain, and stimulating the ECS. Physical exercise has an antioxidant, and anti-inflammatory role and stimulates the release of endogenous opioids. Conclusions: The results obtained from this meta-analysis may contribute to paradigm shifts in clinical practice related to the treatment of pain by PT. TENS, LASER, and physical exercise are effective clinical tool that limits chronic inflammation and pain by involving the ECS. More studies are needed to understand endocannabinoid system involvements in KOA, and that will inspire medical doctors and physiotherapists to improve long-term treatment strategies.

The non-pharmacological treatment of primary dysmenorrhea - efficiency and safety

Primary dysmenorrhea is the most common, though often underdiagnosed, gynecological disorder of women of reproductive age. The disease presents with painful abdominal cramps associated with menstrual bleeding in the absence of pelvic abnormalities. Symptoms are caused primarily by increased levels of prostaglandins produced by the endometrium, which provides hypercontraction of the uterine muscles, ischemia, and pain. Dysmenorrhea is usually treated pharmacologically with non-steroidal anti-inflammatory drugs or hormonal contraception. In particularly severe cases, surgical treatment is also possible. Nonetheless, an increasing amount of studies on non-pharmacological treatments have been published recently. Methods like Transcutaneous Electrical Nerve Stimulation (TENS), acupuncture, continuous topical heat, or exercise and yoga seem to be effective in reducing the symptoms of primary dysmenorrhea. All have an anti-inflammatory effect by lowering prostaglandin levels, but they also contribute to reducing symptoms through other mechanisms. TENS elevates the pain threshold and, together with acupuncture, causes the release of endogenous opioids. Heat, yoga, and acupuncture also lead to increased blood flow in the uterus, reducing hypoxia. Their additional advantage is the low cost and ease of self-use, except for acupuncture, depending on the patient's needs. Side effects of non-pharmacological treatments are usually mild and rarely reported.

Effect and mechanisms of exercise for complex regional pain syndrome.

Complex regional pain syndrome characterized by severe pain and dysfunction seriously affects patients' quality of life. Exercise therapy is gaining attention because it can effectively relieve pain and improve physical function. Based on the previous studies, this article summarized the effectiveness and underlying mechanisms of exercise interventions for complex regional pain syndrome, and described the gradual multistage exercise program. Exercises suitable for patients with complex regional pain syndrome mainly include graded motor imagery, mirror therapy, progressive stress loading training, and progressive aerobic training. In general, exercise training for patients with complex regional pain syndrome not only alleviates pain but also improves physical function and positive mental status. The underlying mechanisms of exercise interventions for complex regional pain syndrome include the remodeling of abnormal central and peripheral nervous system, the regulation of vasodilation and adrenaline levels, the release of endogenous opioids, and the increased anti-inflammatory cytokines. This article provided a clear explanation and summary of the research on exercise for complex regional pain syndrome. In the future, more high-quality studies with sufficient sample sizes may provide more exercise regimens and better evidence of efficacy.

Effects of a peripherally acting µ-opioid receptor antagonist for the prevention of recurrent acute pancreatitis: study protocol for an investigator-initiated, randomized, placebo-controlled, double-blind clinical trial (PAMORA-RAP trial)

BackgroundAcute and chronic pancreatitis constitute a continuum of inflammatory disease of the pancreas with an increasing incidence in most high-income countries. A subset of patients with a history of pancreatitis suffer from recurrence of acute pancreatitis attacks, which accelerate disease progression towards end-stage chronic pancreatitis with loss of exocrine and endocrine function. There is currently no available prophylactic treatment for recurrent acute pancreatitis apart from removing risk factors, which is not always possible. Pain is the primary symptom of acute pancreatitis, which induces the endogenous release of opioids. This may further be potentiated by opioid administration for pain management. Increased exposure to opioids leads to potentially harmful effects on the gastrointestinal tract, including, e.g. increased sphincter tones and decreased fluid secretion, which may impair pancreatic ductal clearance and elevate the risk for new pancreatitis attacks and accelerate disease progression. Peripherally acting µ-opioid receptor antagonists (PAMORAs) have been developed to counteract the adverse effects of opioids on the gastrointestinal tract. We hypothesize that the PAMORA naldemedine will reduce the risk of new pancreatitis attacks in patients with recurrent acute pancreatitis and hence decelerate disease progression.MethodsThe study is a double-blind, randomized controlled trial with allocation of patients to either 0.2 mg naldemedine daily or matching placebo for 12 months. A total of 120 outpatients will be enrolled from five specialist centres in Denmark and Sweden. The main inclusion criteria is a history of recurrent acute pancreatitis (minimum of two confirmed pancreatitis attacks). The primary endpoint is time to acute pancreatitis recurrence after randomization. Secondary outcomes include changes in quality of life, gastrointestinal symptom scores, new-onset diabetes, exocrine pancreatic insufficiency, disease severity, health care utilization, adherence to treatment, and frequency of adverse events. Exploratory outcomes are included for mechanistic linkage and include the progression of chronic pancreatitis-related findings on magnetic resonance imaging (MRI) and changes in circulating blood markers of inflammation and fibrosis.DiscussionThis study investigates if naldemedine can change the natural course of pancreatitis in patients with recurrent acute pancreatitis and improve patient outcomes.Trial registrationEudraCT no. 2021–000069-34. ClinicalTrials.gov NCT04966559. Registered on July 8, 2021.

Treatment of Knee Osteoarthritis with Transcutaneous Electrical Nerve Stimulation

In China, the majority of osteoarthritis patients have the disease in the knee. Clinically, knee osteoarthritis (KOA) often has joint swelling, pain, stiffness, dysfunction and other symptoms, which reduce the patients’ quality of life. There is a trend that osteoarthritis affects more and more young people in China, so it is much more important to treat KOA. Being a cheap and non-surgical option, the transcutaneous electrical nerve stimulation (TENS) has unique advantages in dealing with the pain caused by KOA. This article presents the pathogenesis and pain mechanism of KOA, describes the mechanism of TENS in KOA treatment, discusses the advantages and disadvantages, and proposes some combined treatment methods. Some studies have shown that the pathogenesis of KOA is related to the theory of unequal settlement of knee joints, and the pain comes from cartilage, subchondral bone and synovial membrane lesions. The gate control theory, endogenous opioid peptide release theory and diffuse noxious inhibitory controls theory are considered as the theoretical basis for TENS to inhibit pain. Its effectiveness, adaptability and incidence of adverse reactions are better than using drugs, but it cannot improve walking ability and the range of motion of the joints. Combination therapies of TENS are currently effective for treating KOA, including TENS combined with ultrasound, sodium hyaluronate, massage, functional training and other treatment options.

The role of endogenous opioid neuropeptides in neurostimulation-driven analgesia.

Due to the prevalence of chronic pain worldwide, there is an urgent need to improve pain management strategies. While opioid drugs have long been used to treat chronic pain, their use is severely limited by adverse effects and abuse liability. Neurostimulation techniques have emerged as a promising option for chronic pain that is refractory to other treatments. While different neurostimulation strategies have been applied to many neural structures implicated in pain processing, there is variability in efficacy between patients, underscoring the need to optimize neurostimulation techniques for use in pain management. This optimization requires a deeper understanding of the mechanisms underlying neurostimulation-induced pain relief. Here, we discuss the most commonly used neurostimulation techniques for treating chronic pain. We present evidence that neurostimulation-induced analgesia is in part driven by the release of endogenous opioids and that this endogenous opioid release is a common endpoint between different methods of neurostimulation. Finally, we introduce technological and clinical innovations that are being explored to optimize neurostimulation techniques for the treatment of pain, including multidisciplinary efforts between neuroscience research and clinical treatment that may refine the efficacy of neurostimulation based on its underlying mechanisms.

What is the relationship between physical activity and chronic pain in older adults? A systematic review and meta-analysis protocol

IntroductionChronic pain is highly prevalent in older adults and can cause functional limitations, negatively affecting health and quality of life. Physical activity is a non-pharmacological approach used to prevent chronic...

Green Light Exposure Elicits Anti-inflammation, Endogenous Opioid Release and Dampens Synaptic Potentiation to Relieve Post-surgical Pain

Light therapy improves multiple conditions such as seasonal affective disorders, circadian rhythm dysregulations, and neurodegenerative diseases. However, little is known about its potential benefits in pain management. While current pharmacologic methods are effective in many cases, the associated side effects can limit their use. Non-pharmacological methods would minimize drug dependence, facilitating a reduction of the opioid burden. Green light therapy has been shown to be effective in reducing chronic pain in humans and rodents. However, its underlying mechanisms remain incompletely defined. In this study, we demonstrate that green light exposure reduced postsurgical hypersensitivity in rats. Moreover, this therapy potentiated the antinociceptive effects of morphine and ibuprofen on mechanical allodynia in male rats. Importantly, in female rats, GLED potentiated the antinociceptive effects of morphine but did not affect that of ibuprofen. We showed that green light increases endogenous opioid levels while lessening synaptic plasticity and neuroinflammation. Importantly, this study reveals new insights into how light exposure can affect neuroinflammation and plasticity in both genders. Clinical translation of these results could provide patients with improved pain control and decrease opioid consumption. Given the noninvasive nature of green light, this innovative therapy would be readily implementable in hospitals. PerspectiveThis study provides a potential additional therapy to decrease postsurgical pain. Given the safety, availability, and the efficacy of green light therapy, there is a significant potential for advancing the green light therapy to clinical trials and eventual translation to clinical settings.

86 An Emerging Role of Cannabis as an Anti-Nociceptive Agent in the Treatment of Chronic Back Pain

Abstract Aim This review aims to provide insight into current research regarding a role for the endocannabinoid signalling pathway as a target in the treatment of chronic pain with particular emphasis on potential use as part of the treatment of lower back pain. Method A literature review was conducted using PubMed, Google scholar, and web of science database. The terminologies used were endocannabinoids, cannabis-based medicines, chronic pain, and lower back pain. Results The analgesic effect of cannabinoids is produced by stimulating cannabinoid receptors within the endocannabinoid system. Animal studies show cannabinoid type 2 receptors stimulate the release of endogenous opioids, further enhancing anti-nociceptive properties. Pre-clinical studies demonstrated the amount of morphine required to achieve median effective dose was around 3.6 times lower when morphine was administered with cannabinoids compared to morphine alone. A systematic review of 24 RCT trials and 1334 participants revealed that inhaled cannabis results in improved neuropathic pain symptoms compared to placebo; however, only two studies showed clinical significance. The medicinal use of cannabis comes with adverse effects. Up to a tenth of users are at risk of developing Cannabis use disorder, characterized by psychosocial problems, increased drug-seeking behaviours including craving, withdrawal, and tolerance. Conclusions The use of cannabis is gaining traction as an alternative to opiates despite the ethical and legal considerations. There is scope for cannabinoids to be successful anti-nociceptive agents in the management of chronic back pain. The long-term effects and side effect profile of cannabis- based medicines need more research.

Cellular and circuit diversity determines the impact of endogenous opioids in the descending pain modulatory pathway.

The descending pain modulatory pathway exerts important bidirectional control of nociceptive inputs to dampen and/or facilitate the perception of pain. The ventrolateral periaqueductal gray (vlPAG) integrates inputs from many regions associated with the processing of nociceptive, cognitive, and affective components of pain perception, and is a key brain area for opioid action. Opioid receptors are expressed on a subset of vlPAG neurons, as well as on both GABAergic and glutamatergic presynaptic terminals that impinge on vlPAG neurons. Microinjection of opioids into the vlPAG produces analgesia and microinjection of the opioid receptor antagonist naloxone blocks stimulation-mediated analgesia, highlighting the role of endogenous opioid release within this region in the modulation of nociception. Endogenous opioid effects within the vlPAG are complex and likely dependent on specific neuronal circuits activated by acute and chronic pain stimuli. This review is focused on the cellular heterogeneity within vlPAG circuits and highlights gaps in our understanding of endogenous opioid regulation of the descending pain modulatory circuits.

Mu Opioid Receptor Dynamics in Healthy Volunteers with a History of Childhood Maltreatment.

Evidence suggests that adults with a history of childhood maltreatment, the experience of emotional or physical neglect and/or abuse within the family during childhood, have blunted reward and stress processing, and higher risk of depression. The mu opioid receptor rich nucleus accumbens and amygdala are critical to reward and stress processing respectively. We hypothesized that nucleus accumbens and amygdala mu opioid receptor densities and activity (change in receptor binding due to endogenous opioid release or receptor conformation change) were negatively associated with childhood maltreatment in healthy young adults.Maltreatment was assessed with the Childhood Trauma Questionnaire (CTQ). Healthy participants, n = 75 (52% female) completed [11C]carfentanil positron emission tomography imaging labeling mu opioid receptors. The relationship between CTQ score and binding potential (BPND, proportional to density of unoccupied receptors) was evaluated with a linear mixed effects model.No significant relationship was found between CTQ score and BPND (f = 3.28; df = 1, 73; p = 0.074) or change in BPND (activity) (t = 1.48; df = 198.3; p = 0.14).This is the first investigation of mu opioid receptors in those with childhood maltreatment. We did not identify a significant relationship between mu opioid receptor dynamics and severity of maltreatment in those without psychopathology. Because this cohort has a low CTQ score average, this may indicate that those with low severity of maltreatment may not have associated changes in mu opioid receptor dynamics. Future directions include evaluating a cohort with increased severity of childhood maltreatment.

Life quality, anxiety and depression in patients with сhronic obstructive pulmonary disease (literature review)

Chronic obstructive pulmonary disease (COPD) is an irreversible disease, the main symptoms of which are shortness of breath and cough. With progression, these symptoms worsen the patients’ life quality, limit their physical activity and lead to psychological problems. COPD is the fourth most common disease in the world and one of the leading causes of death. A review of epidemiological studies shows that depression occurs in patients with COPD in 6—80 % of cases, with an average of about 40 %. Also, these patients often have anxiety disorders in 10 to 55 % of cases.158 literature sources in Pubmed database on request COPD AND depression AND anxiety for last 10 years were included to the study and 44 of them were selected for further detailed study.According to the analysis of literature sources, possible relationships between COPD, life quality, anxiety and depressive disorders were found, approaches to their detection, monitoring and treatment were described, as well as the importance of controlling COPD symptoms to improve the patients’ life quality and reduce the manifestations of psychological and mental disorders. Evidence has been found indicating that an increase in physical activity when COPD symptoms are controlled changes the state of functioning of central monoamines, increases the regulation of the hypothalamic­-pituitary-­adrenal system, increases the release of endogenous opioids and decreases the severity of systemic inflammation, which reduces the manifestations of anxiety and depression.Due to the bidirectional relationship of patients’ life quality, depression and anxiety, and COPD, the most effective is an integrated approach that improves the patient’s condition through the impact on both physical and psychological factors. However, there is still a need for randomized trials to definitively study the benefits of psychological, pharmacological, and combined treatments for depression and anxiety disorders in COPD.

Psychological pain and opioid receptors: Reward downshift is disrupted when tested in a context signaling morphine

A sucrose downshift causes a temporary suppression of consumption accompanied by psychological pain, a negative emotion triggered by reward loss. When administered systemically before downshift sessions, opioid agonists reduce and opioid antagonists enhance such behavioral suppression. However, little is known about the effects of signals of opioid drugs on behavior during a reward downshift episode. Research showed that morphine administration can induce a direct effect (e.g., hypoalgesia) followed by a compensatory effect (e.g., hyperalgesia). Therefore, a signal for morphine could elicit either a direct or a compensatory effect. Male Wistar rats were exposed to ten 5-min sessions of access to 32% sucrose in context A, followed by three sessions of access to 4% sucrose in context B. In parallel, animals received pairings between context B and morphine (5 mg/kg, sc) occurring each day immediately after sucrose sessions (contexts were counterbalanced). Control conditions included a saline control (no morphine injected), an unpaired control (morphine injected after exposure to B) tested in A (Experiment 1), and an unpaired control tested in B (Experiment 2). In both experiments, behavioral suppression induced by the 32-to-4% sucrose downshift was attenuated when the downshift occurred in a context previously paired with morphine. These data are consistent with the hypothesis that reward downshift is accompanied by an emotion of negative valence that can be counteracted by the conditioned release of endogenous opioids triggered by signals of morphine, much like it is attenuated by systemic morphine administration. Alternative hypotheses are also discussed.

Aerobic Fitness Is Associated with Cerebral μ-Opioid Receptor Activation in Healthy Humans.

Central μ-opioid receptors (MORs) modulate affective responses to physical exercise. Individuals with higher aerobic fitness report greater exercise-induced mood improvements than those with lower fitness, but the link between cardiorespiratory fitness and the MOR system remains unresolved. Here we tested whether maximal oxygen uptake (V̇O2peak) and physical activity level are associated with cerebral MOR availability and whether these phenotypes predict endogenous opioid release after a session of exercise. We studied 64 healthy lean men who performed a maximal incremental cycling test for V̇O2peak determination, completed a questionnaire assessing moderate-to-vigorous physical activity (MVPA; in minutes per week), and underwent positron emission tomography with [11C]carfentanil, a specific radioligand for MOR. A subset of 24 subjects underwent additional positron emission tomography scan also after a 1-h session of moderate-intensity exercise and 12 of them also after a bout of high-intensity interval training. Higher self-reported MVPA level predicted greater opioid release after high-intensity interval training, and both V̇O2peak and MVPA level were associated with a larger decrease in cerebral MOR binding after aerobic exercise in the ventral striatum, orbitofrontal cortex, and insula. That is, more trained individuals showed greater opioid release acutely after exercise in brain regions especially relevant for reward and cognitive processing. Fitness was not associated with MOR availability. We conclude that regular exercise training and higher aerobic fitness may induce neuroadaptation within the MOR system, which might contribute to improved emotional and behavioral responses associated with long-term exercise.

Risk for opioid misuse in chronic pain patients is associated with endogenous opioid system dysregulation

µ-Opioid receptors (MOR) are a major target of endogenous and exogenous opioids, including opioid pain medications. The µ-opioid neurotransmitter system is heavily implicated in the pathophysiology of chronic pain and opioid use disorder and, as such, central measures of µ-opioid system functioning are increasingly being considered as putative biomarkers for risk to misuse opioids. To explore the relationship between MOR system function and risk for opioid misuse, 28 subjects with chronic nonspecific back pain completed a clinically validated measure of opioid misuse risk, the Pain Medication Questionnaire (PMQ), and were subsequently separated into high (PMQ > 21) and low (PMQ ≤ 21) opioid misuse risk groups. Chronic pain patients along with 15 control participants underwent two separate [11C]-carfentanil positron emission tomography scans to explore MOR functional measures: one at baseline and one during a sustained pain-stress challenge, with the difference between the two providing an indirect measure of stress-induced endogenous opioid release. We found that chronic pain participants at high risk for opioid misuse displayed higher baseline MOR availability within the right amygdala relative to those at low risk. By contrast, patients at low risk for opioid misuse showed less pain-induced activation of MOR-mediated, endogenous opioid neurotransmission in the nucleus accumbens. This study links human in vivo MOR system functional measures to the development of addictive disorders and provides novel evidence that MORs and µ-opioid system responsivity may underlie risk to misuse opioids among chronic pain patients.