Release Of Endogenous Opioids Research Articles

Association Between Placebo-Activated Neural Systems and Antidepressant Responses: Neurochemistry of Placebo Effects in Major Depression.

High placebo responses have been observed across a wide range of pathologies, severely impacting drug development. To examine neurochemical mechanisms underlying the formation of placebo effects in patients with major depressive disorder (MDD). In this study involving 2 placebo lead-in phases followed by an open antidepressant administration, we performed a single-blinded 2-week crossover randomized clinical trial of 2 identical oral placebos (described as having either active or inactive fast-acting antidepressant-like effects) followed by a 10-week open-label treatment with a selective serotonin reuptake inhibitor or, in some cases, another agent as clinically indicated. The volunteers (35 medication-free patients with MDD at a university health system) were studied with positron emission tomography and the µ-opioid receptor-selective radiotracer [11C]carfentanil after each 1-week inactive and active oral placebo treatment. In addition, 1 mL of isotonic saline was administered intravenously within sight of the volunteer during positron emission tomographic scanning every 4 minutes over 20 minutes only after the 1-week active placebo treatment, with instructions that the compound may be associated with the activation of brain systems involved in mood improvement. This challenge stimulus was used to test the individual capacity to acutely activate endogenous opioid neurotransmision under expectations of antidepressant effect. Changes in depressive symptoms in response to active placebo and antidepressant. Baseline and activation measures of µ-opioid receptor binding. Higher baseline µ-opioid receptor binding in the nucleus accumbens was associated with better response to antidepressant treatment (r = 0.48; P = .02). Reductions in depressive symptoms after 1 week of active placebo treatment, compared with the inactive, were associated with increased placebo-induced µ-opioid neurotransmission in a network of regions implicated in emotion, stress regulation, and the pathophysiology of MDD, namely, the subgenual anterior cingulate cortex, nucleus accumbens, midline thalamus, and amygdala (nucleus accumbens: r = 0.6; P < .001). Placebo-induced endogenous opioid release in these regions was associated with better antidepressant treatment response, predicting 43% of the variance in symptom improvement at the end of the antidepressant trial. These data demonstrate that placebo-induced activation of the µ-opioid system is implicated in the formation of placebo antidepressant effects in patients with MDD and also participate in antidepressant responses, conferring illness resiliency, during open administration. clinicaltrials.gov Identifier:NCT02178696.

Ictal analgesia in temporal lobe epilepsy – The mechanism of seizure-related burns

Seizure-related injuries have major impact in the excess mortality and morbidity of epilepsy patients. Experimental data suggest that analgesia may develop during seizures contributing to the severity of seizure-related accidents, especially burns. We aimed to identify those seizure-types that may lead to burn-injuries by seizure-related analgesia.In our tertiary epilepsy centre, we asked 100 epilepsy patients having a history of seizure-related injury, to complete our burn-and-pain questionnaire. Fifty-one patients completed the survey; their epileptology data were collected and those with a seizure-related burn were interviewed.Forty-two out of the 51 patients (82%) had partial epilepsy and 9 (18%) had idiopathic generalised epilepsy. Twenty-six persons (51%) reported decreased pain perception during or after seizures in general. Twelve patients (23%) had suffered one or more seizure-related burn. Five of them fell onto a hot surface or fire accidentally, during generalized tonic–clonic seizures. Seven out of the 12 burnt patients (58%) grasped a hot object or reached into boiling fluid during complex partial seizures; without experiencing-, or reacting in response to pain. These patients had temporal lobe epilepsy, 5 of them had left temporal seizure onset.Our hypothesis based on the circumstantial analysis of our patients’ burn-injuries; is that temporal lobe seizures may cause ictal/postictal analgesia. It may be caused by the seizure-related epileptic facilitation of the periaqueductal gray matter; the central pain-inhibiting structure of the brain. Seizure-related endogenous opioid-release my have a contributory role in inhibiting pain-perception.Ictal analgesia warrants better burn-prevention in temporal lobe epilepsy patients. Understanding the mechanism of ictal analgesia and specifying those seizures-types prone to cause it; may help indentifying human pain-inhibiting pathways.

μ-Opioid Receptor Gene A118 G Variants and Persistent Pain Symptoms Among Men and Women Experiencing Motor Vehicle Collision

The μ-opioid receptor 1 (OPRM1) binds endogenous opioids. Increasing evidence suggests that endogenous OPRM1 agonists released at the time of trauma may contribute to the development of posttraumatic musculoskeletal pain (MSP). In this prospective observational study, we evaluated the hypothesis that individuals with an AG or GG genotype at the OPRM1 A118 G allele, which results in a reduced response to opioids, would have less severe MSP 6 weeks after motor vehicle collision (MVC). Based on previous evidence, we hypothesized that this effect would be sex-dependent and most pronounced among women with substantial peritraumatic distress. European American men and women ≥18 years of age presenting to the emergency department after MVC and discharged to home after evaluation (N = 948) were enrolled. Assessments included genotyping and 6-week evaluation of overall MSP severity (0–10 numeric rating scale). In linear regression modeling, a significant A118 G Allele × Sex interaction was observed: an AG/GG genotype predicted reduced MSP severity among women with substantial peritraumatic distress (β = –.925, P = .014) but not among all women. In contrast, men with an AG/GG genotype experienced increased MSP severity at 6 weeks (β = .827, P = .019). Further studies are needed to understand the biologic mechanisms mediating observed sex differences in A118 G effects. PerspectiveThese results suggest a sex-dependent mechanism by which an emotional response to trauma (distress) contributes to a biologic mechanism (endogenous opioid release) that increases MSP in the weeks after stress exposure. These results also support the hypothesis that endogenous opioids influence pain outcomes differently in men and women.

Involvement of endogenous opioid peptides in the peripheral antinociceptive effect induced by the coffee specific diterpene kahweol.

Kahweol is a diterpene present in the oil derived from coffee beans. Although several pharmacological activities of kahweol are already well described in the literature, no study was done in order to assess the analgesic activity of this substance. Thus, the aim of this study was to investigate the possible peripheral antinociceptive effect of kahweol. Considering that the opioid peptides have been implicated in peripheral antinociception induced by non-opioidergic compounds, the present study also evaluated the endogenous opioids involvement in this effect. The rat paw pressure test was used, and hyperalgesia was induced by intraplantar injection of prostaglandin E2 (2μg/paw). All drugs were administered subcutaneously in the hindpaws of male Wistar rats. The expression of β-endorphin was examined by immunohistochemistry in the skin tissue samples of the plantar surface of rat right hindpaws. Intraplantar injection of kahweol (40 and 80μg) induced significant peripheral antinociception. The antinociceptive effect of kahweol was due to a local peripheral action because the higher dose (80μg/paw) did not produce any effect in the contralateral paw. The opioid receptor antagonist naloxone (50 and 100μg/paw) prevented action of kahweol (80μg/paw) and the aminopeptidases inhibitor bestatin (400μg/paw) potentiated the antinociceptive effect of kahweol (40μg/paw). Furthermore, kahweol treatment increased the intensity of β-endorphin immunoreactivity in the epithelium of rat paws. The results discussed here provide evidence that kahweol treatment has peripheral antinociceptive effect and suggest that this effect is mediated by the release of endogenous opioids.

Placebo analgesia: understanding the mechanisms.

Expectations of pain relief drive placebo analgesia. Understanding how expectations of improvement trigger distinct biological systems to shape therapeutic analgesic outcomes has been the focus of recent pharmacologic and neuroimaging studies in the field of pain. Recent findings indicate that placebo effects can imitate the actions of real painkillers and promote the endogenous release of opioids and nonopioids in humans. Social support and observational learning also contribute to placebo analgesic effects. Distinct psychological traits can modulate expectations of analgesia, which facilitate brain pain control mechanisms involved in pain reduction. Many studies have highlighted the importance and clinical relevance of these responses. Gaining deeper understanding of these pain modulatory mechanisms has important implications for personalizing patient pain management.

It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder

The μ-opioid receptor (MOR) system, well known for dampening physical pain, is also hypothesized to dampen 'social pain.' We used positron emission tomography scanning with the selective MOR radioligand [(11)C]carfentanil to test the hypothesis that MOR system activation (reflecting endogenous opioid release) in response to social rejection and acceptance is altered in medication-free patients diagnosed with current major depressive disorder (MDD, n=17) compared with healthy controls (HCs, n=18). During rejection, MDD patients showed reduced endogenous opioid release in brain regions regulating stress, mood and motivation, and slower emotional recovery compared with HCs. During acceptance, only HCs showed increased social motivation, which was positively correlated with endogenous opioid release in the nucleus accumbens, a reward structure. Altered endogenous opioid activity in MDD may hinder emotional recovery from negative social interactions and decrease pleasure derived from positive interactions. Both effects may reinforce depression, trigger relapse and contribute to poor treatment outcomes.

Mu Opioid Receptor Binding Correlates with Nicotine Dependence and Reward in Smokers.

The rewarding effects of nicotine are associated with activation of nicotine receptors. However, there is increasing evidence that the endogenous opioid system is involved in nicotine's rewarding effects. We employed PET imaging with [11C]carfentanil to test the hypotheses that acute cigarette smoking increases release of endogenous opioids in the human brain and that smokers have an upregulation of mu opioid receptors (MORs) when compared to nonsmokers. We found no significant changes in binding potential (BPND) of [11C]carfentanil between the placebo and the active cigarette sessions, nor did we observe differences in MOR binding between smokers and nonsmokers. Interestingly, we showed that in smokers MOR availability in bilateral superior temporal cortices during the placebo condition was negatively correlated with scores on the Fagerström Test for Nicotine Dependence (FTND). Also in smokers, smoking-induced decreases in [11C]carfentanil binding in frontal cortical regions were associated with self-reports of cigarette liking and wanting. Although we did not show differences between smokers and nonsmokers, the negative correlation with FTND corroborates the role of MORs in superior temporal cortices in nicotine addiction and provides preliminary evidence of a role of endogenous opioid signaling in frontal cortex in nicotine reward.

Renin-angiotensin system in pain: existing in a double life?

Apart from the well-documented role of the renin-angiotensin-aldosterone system (RAAS) in regulating the blood pressure and other related parameters, its role in modulating different physiological/pathological functions, including pain, has also been described. Like its dual role in regulating stress-related anxiety and cognitive functions, its dual role has also been documented in pain modulation in different disease states. Drugs blocking the RAAS activation, viz., renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, AT(1) receptor antagonists and aldosterone antagonists, have been shown to produce beneficial effects in migraine and neuropathic and nociceptive pain. Their beneficial effects have been mainly attributed to inhibition of the inflammatory cascade of reactions by inhibiting the generation of key cytokines, including tumor necrosis factor (TNF)-α. On the contrary, clinical as well as preclinical studies have also shown the pain-inducing actions of renin-angiotensin system (RAS) blocking drugs. Furthermore, the pain-relieving actions of angiotensin II (AngII) and pain-inducing actions of AT(1) blockers have also been described. The pain-inducing actions of ACE inhibitors have been mainly attributed to interference with metabolism of bradykinin and substance P, while the analgesic actions of AngII have been mainly related to activation of brain localized AT(2) receptors and release of endogenous opioids. The present review describes the dual role of the RAAS in different states of pain.

Effects of naltrexone on neural and subjective response to alcohol in treatment-seeking alcohol-dependent patients.

Positively reinforcing properties of alcohol are in part mediated by activation of the ventral striatum (VS). Alcohol-induced release of endogenous opioids is thought to contribute to this response. Preclinical studies show that the opioid antagonist naltrexone (NTX) can block this cascade, but its ability to do so in treatment-seeking alcoholics has not been examined. Our objective was to study the effects of NTX on alcohol-induced VS activation and on amygdala response to affective stimuli in treatment-seeking alcohol-dependent inpatients. Sixty-three treatment-seeking alcoholics were randomized to receive NTX (50mg) or placebo (PLC) daily. On Day 7, participants underwent an alcohol cue reactivity session, and craving was measured using the Penn Alcohol Craving Scale. On Day 9, participants received a saline infusion followed by an alcohol infusion and also viewed affective stimuli in a magnetic resonance scanner. Irrespective of medication treatment condition, the alcohol infusion did not activate the VS in the alcohol-dependent patients. Unexpectedly, VS activation was greater in NTX treated patients than in the PLC group. NTX treated patients also reported increased craving in response to alcohol cue exposure, and increased subjective response to alcohol ("high" and "intoxicated") compared to PLC subjects. No significant effects of alcohol infusion on brain response to affective stimuli were in the NTX or PLC groups. Unlike previous findings in social drinkers, a moderate level of intoxication did not activate the VS in treatment-seeking alcoholics. This is likely to reflect tolerance to the positively reinforcing properties of alcohol in this clinical population. Our findings may help explain the efficacy of NTX to reduce heavy drinking, but not to maintain abstinence.

Effects of the Mu opioid receptor polymorphism (OPRM1 A118G) on pain regulation, placebo effects and associated personality trait measures.

Mu-opioid receptors (MOPRs) are critically involved in the modulation of pain and analgesia, and represent a candidate mechanism for the development of biomarkers of pain conditions and their responses to treatment. To further understand the human implications of genetic variation within the opioid system in pain and opioid-mediated placebo responses, we investigated the association between the functional single-nucleotide polymorphism (SNP) in the μ-opioid receptor gene (OPRM1), A118G, and psychophysical responses, personality traits, and neurotransmitter systems (dopamine (DA), opioid) related to pain and placebo analgesia. OPRM1 G carriers, compared with AA homozygotes, showed an overall reduction of baseline μ-opioid receptor availability in regions implicated in pain and affective regulation. In response to a sustained painful stimulus, we found no effect of A118G on pain-induced endogenous opioid release. Instead, AA homozygotes showed a blunted DA response in the nucleus accumbens (NAc) in response to the pain challenge. After placebo administration, G carriers showed more pronounced mood disturbances and lower placebo-induced μ-opioid system activation in the anterior insula (aINS), the amygdala (AMY), the NAc, the thalamus (THA), and the brainstem, as well as lower levels of DA D2/3 activation in the NAc. At a trait level, G carriers reported higher NEO-Neuroticism scores; a personality trait previously associated with increased pain and lower placebo responses, which were negatively correlated with baseline μ-opioid receptor availability in the aINS and subgenual anterior cingulate cortex (sgACC). Our results demonstrate that the A118G OPRM1 polymorphism contributes to interindividual variations in the function of neurotransmitters responsive to pain (endogenous opioid and dopamine), as well as their regulation through cognitive-emotional influences in the context of therapeutic expectations, the so-called placebo effect. These effects are relevant to human vulnerability to disease processes where these neurotransmitters have a role, such as persistent pain, mood, and substance use disorders, and responses to their treatments.

P.6.f.002 Endogenous opioid release in pathological gamblers after an oral amphetamine challenge: a [11C]carfentanil PET study

P.6.f.002 Endogenous opioid release in pathological gamblers after an oral amphetamine challenge: a [11C]carfentanil PET study

Significance of neuronal cytochrome P450 activity in opioid-mediated stress-induced analgesia

Stressful environmental changes can suppress nociceptive transmission, a phenomenon known as “stress-induced analgesia”. Depending on the stressor and the subject, opioid or non-opioid mechanisms are activated. Brain μ opioid receptors mediate analgesia evoked either by exogenous agents (e.g. morphine), or by the release of endogenous opioids following stressful procedures. Recent work with morphine and neuronal cytochrome P450 (P450)-deficient mice proposed a signal transduction role for P450 enzymes in µ analgesia. Since µ opioid receptors also mediate some forms of stress-induced analgesia, the present studies assessed the significance of brain P450 activity in opioid-mediated stress-induced analgesia. Two widely-used models of opioid stress-induced analgesia (restraint and warm water swim) were studied in both sexes of wild-type control and P450-deficient (Null) mice. In control mice, both stressors evoked moderate analgesic responses which were blocked by pretreatment with the opioid antagonist naltrexone, confirming the opioid nature of these responses. Consistent with literature, sex differences (control female>control male) were seen in swim-induced, but not restraint-induced, analgesia. Null mice showed differential responses to the two stress paradigms. As compared with control subjects, Null mice showed highly attenuated restraint-induced analgesia, showing a critical role for neuronal P450s in this response. However, warm water swim-induced analgesia was unchanged in Null vs. control mice. Additional control experiments confirmed the absence of morphine analgesia in Null mice. These results are the first to show that some forms of opioid-mediated stress-induced analgesia require brain neuronal P450 activity.

Imaging endogenous opioid peptide release with [11C]carfentanil and [3H]diprenorphine: influence of agonist-induced internalization.

Understanding the cellular processes underpinning the changes in binding observed during positron emission tomography neurotransmitter release studies may aid translation of these methodologies to other neurotransmitter systems. We compared the sensitivities of opioid receptor radioligands, carfentanil, and diprenorphine, to amphetamine-induced endogenous opioid peptide (EOP) release and methadone administration in the rat. We also investigated whether agonist-induced internalization was involved in reductions in observed binding using subcellular fractionation and confocal microscopy. After radioligand administration, significant reductions in [(11)C]carfentanil, but not [(3)H]diprenorphine, uptake were observed after methadone and amphetamine pretreatment. Subcellular fractionation and in vitro radioligand binding studies showed that amphetamine pretreatment only decreased total [(11)C]carfentanil binding. In vitro saturation binding studies conducted in buffers representative of the internalization pathway suggested that μ-receptors are significantly less able to bind the radioligands in endosomal compared with extracellular compartments. Finally, a significant increase in μ-receptor-early endosome co-localization in the hypothalamus was observed after amphetamine and methadone treatment using double-labeling confocal microscopy, with no changes in δ- or κ-receptor co-localization. These data indicate carfentanil may be superior to diprenorphine when imaging EOP release in vivo, and that alterations in the ability to bind internalized receptors may be a predictor of ligand sensitivity to endogenous neurotransmitter release.

Endogenous opioid-induced neuroplasticity of dopaminergic neurons in the ventral tegmental area influences natural and opiate reward.

Natural reward and drugs of abuse converge on the mesolimbic pathway and activate common mechanism of neural plasticity in the nucleus accumbens. Chronic exposure to opiates induces plasticity in dopaminergic neurons of the ventral tegmental area (VTA), which regulates morphine reward tolerance. Here, we test the hypotheses that mating-induced release of endogenous opioids in the VTA causes morphological changes of VTA dopamine cells in male rats, which in-turn regulate the long-term expression of experience-induced reinforcement of sexual behavior. First, sexual experience decreased VTA dopamine soma size 1 and 7 days, but not 30 days after the last mating session. This effect was blocked with naloxone before each mating session; thus, VTA dopamine cell plasticity was dependent on action of endogenous opioids. In turn, VTA plasticity was associated with altered opiate reward, as sexually experienced males did not form conditioned place preference for 0.5 mg/kg morphine. Next, it was determined whether endogenous opioid action mediates sexual reward and memory in male rats treated with naloxone during mating experience, either systemically or intra-VTA. Naloxone did not prevent the initial experience-induced facilitation of sexual behavior over repeated mating sessions, or conditioned place preference for mating. However, naloxone treatment attenuated the longer-term expression of experience-induced facilitation of sexual behavior and neural activation in mesolimbic areas induced by mating-associated conditioned cues. Together, these data demonstrate that endogenous opioids during mating induce neural plasticity in VTA dopamine neurons that appear critical for morphine reward and long-term memory for natural reward behavior.

Amphetamine induced endogenous opioid release in the human brain detected with [¹¹C]carfentanil PET: replication in an independent cohort.

This study aimed to replicate a previous study which showed that endogenous opioid release, following an oral dose of amphetamine, can be detected in the living human brain using [11C]carfentanil positron emission tomography (PET) imaging. Nine healthy volunteers underwent two [11C]carfentanil PET scans, one before and one 3 h following oral amphetamine administration (0.5 mg/kg). Regional changes in [11C]carfentanil BPND from pre- to post-amphetamine were assessed. The amphetamine challenge led to significant reductions in [11C]carfentanil BPND in the putamen, thalamus, frontal lobe, nucleus accumbens, anterior cingulate, cerebellum and insula cortices, replicating our earlier findings. None of the participants experienced significant euphoria/'high', supporting the use of oral amphetamine to characterize in vivo endogenous opioid release following a pharmacological challenge. [11C]carfentanil PET is able to detect changes in binding following an oral amphetamine challenge that reflects endogenous opioid release and is suitable to characterize the opioid system in neuropsychiatric disorders.

Understanding placebo and nocebo responses for pain management.

Placebo analgesia makes individuals experience relief of their pain simply by virtue of the anticipation of a benefit. A reduction of pain can occur also when placebos follow the administration of active and effective painkillers. In fact, studies indicate that placebos mimic the action of active treatments and promote the endogenous release of opioids in both humans and animals. Finally, social support and observational learning also lead to analgesic effects. Thus, different psychological factors and situations induce expectations of analgesia facilitating the activation of the top-down systems for pain control along with the release of endogenous mediators crucially involved in placebo-induced benefits. Recent scientific investigation in the field of brain imaging is opening new avenues to understanding the cognitive mechanisms and neurobiological substrates of expectation-induced pain modulation. Gaining deeper knowledge of top-down mechanisms of pain modulation has enormous implications for personalizing and optimizing pain management.

Kappa-Opioid Receptor Antagonism: A Mechanism for Treatment of Relief Drinking?

Of recreational users of alcohol, 15% at some point go on to develop a pattern of alcohol seeking and taking that continues despite adverse consequences—that is, alcohol addiction or simply alcoholism. This proportion is not much different from what is seen with other drugs of abuse, but more than half of all Americans $12 years old report being current drinkers. As a result, in the United States, 12 million people have a current diagnosis of alcoholism, accounting for a greater disease burden than all illicit drugs combined. Few evidencebased treatments are currently available for these patients. Efficacy of existing treatments is limited further by the heterogeneity of alcoholism. Optimal clinical management of these patients ultimately requires personalized approaches that match treatments to pathophysiologically relevant individual characteristics. Some of these characteristics are clearly genetic, but personalized therapies also need to take in account neuroadaptations that develop over time as a result of alcohol use itself. Research over the past decade has demonstrated that the motivational mechanisms driving alcohol use undergo a shift over the course of the addictive process. In initial stages of alcohol use, positively reinforcing, or rewarding, properties of alcohol dominate. These are mediated partly by alcohol-induced release of endogenous opioids that activate mu opioid receptors, a mechanism targeted by the U.S. Food and Drug Administration–approved opioid antagonist naltrexone. However, with increased duration of brain alcohol exposure and dependence, alcohol consumption becomes increasingly driven by negatively reinforcing actions of alcohol. During this stage, negative emotional states emerge in the absence of alcohol. Because these can be temporarily alleviated by resuming alcohol intake, they introduce a novel, powerful incentive for alcohol consumption—often called the “dark side of addiction.” There are currently no clinically approved medications targeting this type of “relief drinking.” Antagonists for corticotropin-releasing factor receptor 1 (CRF1) have been pursued for some time for their potential in this regard, but along the way, other neurochemical mechanisms have emerged that seem to hold similar promise. In one of the most exciting developments, Walker and Koob (1) discovered that intracerebroventricular administration of the kappa opioid receptor (KOR) antagonist norbinaltorphimine selectively suppresses dependence-induced escalation of alcohol consumption in a manner similar to CRF1 antagonists. In this issue of Biological Psychiatry, Kissler et al. (2) provide an

P.3.008 Endogenous opioid release in pathological gamblers after an oral amphetamine challenge: a [C]carfentanil PET study

P.3.008 Endogenous opioid release in pathological gamblers after an oral amphetamine challenge: a [C]carfentanil PET study

The Potential Role of the Endogenous Opioid System in the Antidepressant Effect of Ketamine

The noncompetitive NMDA receptor blocker ketamine provides significant improvement to patients suffering from depression but its mechanistic pathways are not fully understood. The endogenous opioid system is known to be dysregulated in patients with depression. Ketamine is known to interact with the opioid system either directly or indirectly through the release of endogenous opioids. In this review, I am discussing the potential role that might be played by the endogenous opioid system in conferring the antidepressant effect of ketamine and emphasizing that the modulation of the opioid system by ketamine warrants in-depth investigation for potential antidepressant effect.

Low‐ and high‐frequency transcutaneous electrical acupoint stimulation induces different effects on cerebral μ‐opioid receptor availability in rhesus monkeys

Although systematic studies have demonstrated that acupuncture or electroacupuncture (EA) analgesia is based on their accelerating endogenous opioid release to activate opioid receptors and that EA of different frequencies is mediated by different opioid receptors in specific areas of the central nervous system, there is little direct, real-time evidence to confirm this in vivo. The present study was designed to investigate the effects of transcutaneous electrical acupoint stimulation (TEAS), an analogue of EA, at low and high frequencies on μ-opioid receptor (MOR) availability in the brain of rhesus monkeys. Monkeys underwent 95-min positron emission tomography (PET) with (11) C-carfentanil three times randomly while receiving 0, 2, or 100 Hz TEAS, respectively. Each TEAS was administered in the middle 30 min during the 95-min PET scan, and each session of PET and TEAS was separated by at least 2 weeks. The results revealed that 2 Hz but not 100 Hz TEAS evoked a significant increase in MOR binding potential in the anterior cingulate cortex, the caudate nucleus, the putamen, the temporal lobe, the somatosensory cortex, and the amygdala compared with 0 Hz TEAS. The effect remained after the end of TEAS in the anterior cingulate cortex and the temporal lobe. The selective increase in MOR availability in multiple brain regions related to pain and sensory processes may play a role in mediating low-frequency TEAS efficacy.