Opioid Function Research Articles

Anger regulation style, anger arousal and acute pain sensitivity: evidence for an endogenous opioid “triggering” model

Findings suggest that greater tendency to express anger is associated with greater sensitivity to acute pain via endogenous opioid system dysfunction, but past studies have not addressed the role of anger arousal. We used a 2×2 factorial design with Drug Condition (placebo or opioid blockade with naltrexone) crossed with Task Order (anger-induction/pain-induction or pain-induction/anger-induction), and with continuous Anger-out Subscale scores. Drug×Task Order×Anger-out Subscale interactions were tested for pain intensity during a 4-min ischemic pain task performed by 146 healthy people. A significant Drug×Task Order×Anger-out Subscale interaction was dissected to reveal different patterns of pain intensity changes during the pain task for high anger-out participants who underwent pain-induction prior to anger-induction compared to those high in anger-out in the opposite order. Namely, when angered prior to pain, high anger-out participants appeared to exhibit low pain intensity under placebo that was not shown by high anger-out participants who received naltrexone. Results hint that people with a pronounced tendency to express anger may suffer from inadequate opioid function under simple pain-induction, but may experience analgesic benefit to some extent from the opioid triggering properties of strong anger arousal.

Individual differences in endogenous opioid function predict analgesic responses to morphine

Factors contributing to differential responses to opioid analgesic medications across individuals are not well understood. This study tested whether individual differences in endogenous opioid systems contribute to variability in responses to a prototypic exogenous opioid analgesic. Participants included 18 healthy individuals and 26 individuals with chronic low back pain (LBP), all using no opioid analgesics. Participants attended 3 identical sessions during which they received either intravenous naloxone (8mg), morphine sulfate (0.08mg/kg), or saline placebo, and then underwent an ischemic forearm pain task followed by a computerized heat pain task (Medoc TSA-II).

Opioid Function Is Dysregulated Subsequent to Early Social Trauma: Healthy Young Adults’ Response to a Buprenorphine Challenge

Panksepp’s separation-distress model of depression posits that endogenous opioid systems become dysregulated subsequent to early social trauma and that this dysregulation constitutes a risk factor for depression. We tested an aspect of this model by recruiting medically and psychiatrically healthy young adults (N = 32) who differed on one key criterion—exposure to early social trauma. In terms of core affective personality traits as measured by the Affective Neuroscience Personality Scales (ANPS), those not exposed to early social trauma scored significantly higher on SEEKING; the groups did not differ on SADNESS. Importantly, the groups also responded differently to a low-dose opioid challenge (0.2 mg sublingual buprenorphine vs. placebo). Buprenorphine administration had little effect on emotion in controls, but it reduced experience of both positive and negative emotion in trauma-exposed participants. The latter also showed a significant negative bias in social cognition that was not attenuated by buprenorphine, whereas controls were more likely to show a positive bias on buprenorphine (relative to trauma-exposed participants). The groups’ differing responses to buprenorphine suggest that their opioid systems are functioning differently. These data constitute preliminary proof of concept for a key aspect of the model. Further investigation of the role of endogenous opioids in depression subsequent to early social trauma is warranted.

Effects of estrogen and opioid blockade on blood pressure reactivity to stress in postmenopausal women

Estrogen may influence coronary heart disease risk in women through the effects of endogenous opioids on autonomic control of blood pressure. In a randomized, placebo-controlled trial, we examined the combined effects of estrogen and the opioid antagonist, naltrexone, on blood pressure responses to psychological stress in 42 postmenopausal women. After 3months of estrogen or estrogen plus progestin (hormone replacement therapy; n=27) or placebo replacement, participants completed a mental arithmetic task after administration of .7mg/kg oral naltrexone or placebo. Systolic blood pressure (SBP), diastolic blood pressure, mean arterial pressure and heart rate (HR) were measured at rest and during the arithmetic stressor. Stress produced significant increases in circulatory measures regardless of estrogen condition or opioid blockade (p's<.001). Interestingly, there was an estrogen by naltrexone interaction on SBP reactivity scores [F(1,38)=4.36, p<.05], where women on estrogen with intact opioid receptors showed the largest SBP responses to stress, compared with all other conditions. This is consistent with some studies of premenopausal women, suggesting that estrogens may alter opioid function during stress. The interaction between estrogen and endogenous opioids may explain sex differences in opioid effects on stress reactivity in younger premenopausal women.

Importance of sex to pain and its amelioration; relevance of spinal estrogens and its membrane receptors

Estrogens have a multitude of effects on opioid systems and are thought to play a key role in sexually dimorphic nociception and opioid antinociception. Heretofore, classical genomic actions of estrogens are largely thought to be responsible for the effects of these steroids on nociception and opioid antinociception. The recent discovery that estrogens can also activate estrogen receptors that are located in the plasma membrane, the effects of which are manifest in seconds to minutes instead of hours to days has revolutionized our thinking concerning the ways in which estrogens are likely to modulate pain responsiveness and the dynamic nature of that modulation. This review summarizes parameters of opioid functionality and nociception that are subject to modulation by estrogens, underscoring the added dimensions of such modulation that accrues from rapid membrane estrogen receptor signaling. Implications of this mode of signaling regarding putative sources of estrogens and its degradation are also discussed.

Cholesterol level influences opioid signaling in cell models and analgesia in mice and humans

Cholesterol regulates the signaling of µ-opioid receptor in cell models, but it has not been demonstrated in mice or humans. Whether cholesterol regulates the signaling by mechanisms other than supporting the entirety of lipid raft microdomains is still unknown. By modulating cholesterol-enriched lipid raft microdomains and/or total cellular cholesterol contents in human embryonic kidney cells stably expressing µ-opioid receptor, we concluded that cholesterol stabilized opioid signaling both by supporting the lipid raft's entirety and by facilitating G protein coupling. Similar phenomena were observed in the primary rat hippocampal neurons. In addition, reducing the brain cholesterol level with simvastatin impaired the analgesic effect of opioids in mice, whereas the opioid analgesic effect was enhanced in mice fed a high-cholesterol diet. Furthermore, when the records of patients were analyzed, an inverse correlation between cholesterol levels and fentanyl doses used for anesthesia was identified, which suggested the mechanisms above could also be applicable to humans. Our results identified the interaction between opioids and cholesterol, which should be considered in clinics as a probable route for drug-drug interaction. Our studies also suggested that a low cholesterol level could lead to clinical issues, such as the observed impairment in opioid functions.

OA08.01. Cholecystokinin antagonizes opioid function during electroacupuncture inhibitory effect on pressor reflex in rats

Purpose Acupuncture or electroacupuncture (EA) is increasingly being accepted as a viable therapy in the United States and may serve as an alternative treatment to drug therapy in patients with mild to moderate hypertension. We have demonstrated that EA acts through an opioid mechanism in the rostral ventrolateral medulla (rVLM) to inhibit sympathoexcitatory reflexes induced by gastric distention. Cholecystokinin octapeptide (CCK-8), a gastrointestinal peptide hormone, is present throughout the central nervous system and mediates pain and anxiety. CCK-8 interacts with CCK1 and CCK2 receptors. The present study investigated the hypothesis that CCK-8 in the rVLM limits the modulatory action of EA effect on sympathoexcitatory responses.

GRK2 Protein-mediated Transphosphorylation Contributes to Loss of Function of μ-Opioid Receptors Induced by Neuropeptide FF (NPFF2) Receptors

Neuropeptide FF (NPFF) interacts with specific receptors to modulate opioid functions in the central nervous system. On dissociated neurons and neuroblastoma cells (SH-SY5Y) transfected with NPFF receptors, NPFF acts as a functional antagonist of μ-opioid (MOP) receptors by attenuating the opioid-induced inhibition of calcium conductance. In the SH-SY5Y model, MOP and NPFF(2) receptors have been shown to heteromerize. To understand the molecular mechanism involved in the anti-opioid activity of NPFF, we have investigated the phosphorylation status of the MOP receptor using phospho-specific antibody and mass spectrometry. Similarly to direct opioid receptor stimulation, activation of the NPFF(2) receptor by [D-Tyr-1-(NMe)Phe-3]NPFF (1DMe), an analog of NPFF, induced the phosphorylation of Ser-377 of the human MOP receptor. This heterologous phosphorylation was unaffected by inhibition of second messenger-dependent kinases and, contrarily to homologous phosphorylation, was prevented by inactivation of G(i/o) proteins by pertussis toxin. Using siRNA knockdown we could demonstrate that 1DMe-induced Ser-377 cross-phosphorylation and MOP receptor loss of function were mediated by the G protein receptor kinase GRK2. In addition, mass spectrometric analysis revealed that the phosphorylation pattern of MOP receptors was qualitatively similar after treatment with the MOP agonist Tyr-D-Ala-Gly (NMe)-Phe-Gly-ol (DAMGO) or after treatment with the NPFF agonist 1DMe, but the level of multiple phosphorylation was more intense after DAMGO. Finally, NPFF(2) receptor activation was sufficient to recruit β-arrestin2 to the MOP receptor but not to induce its internalization. These data show that NPFF-induced heterologous desensitization of MOP receptor signaling is mediated by GRK2 and could involve transphosphorylation within the heteromeric receptor complex.

Cholecystokinin Antagonizes Opioid Function during Electroacupuncture Modulation of Reflex Hypertension in Rats

Hypertension is one of the greatest causes of death in middle‐aged and elderly North Americans, but current western medical therapies are not fully effective. Acupuncture or electroacupuncture (EA) is increasingly being accepted as a viable therapy in the United States and may serve as an alternative treatment to drug therapy in patients with mild to moderate hypertension. We have demonstrated that EA acts through an opioid mechanism in rostral ventrolateral medulla (rVLM) to inhibit sympathoexcitatory reflexes induced by gastric distention. Cholecystokinin octapeptide (CCK‐8), a gastrointestinal peptide hormone, is present throughout the central nervous system and mediates pain and anxiety. CCK‐8 interacts with CCK1 and CCK2 receptors. The present study investigated the hypothesis that CCK‐8 in the rVLM limits the modulatory action of EA effect on sympathoexcitatory responses. Experiments were performed on male rats anesthetized with ketamine and α‐chloralose who were subjected to repeated gastric distension every 10 minutes. EA ( 2Hz, 0.5ms, 1–4mA) at Jianshi‐Neiguan (P5–P6) acupoints was applied for 30 min followed by microinjection of CCK‐8 (0.15mM, 50 nl) into the rVLM in 7 rats reversed the EA modulatory response from (11.0 ± 2.0 ) to (19.1 ± 2.8) mmHg. Saline injections into the rVLM at the end of 30 min EA did not influence the prolonged inhibition of reflex elevations in blood pressure in five other animals. Alternatively, devazepide (0.5 mM, 50 nl), a CCK1 antagonist microinjected into the rVLM of six rats that initially did not respond to 30 min of EA led to conversion during a second application of EA. Micoinjection of the vehicle of devazepide (50 nl ) into rVLM did not modify the nonresponsiveness to EA application (n=2). These data suggest that CCK‐8 through its action on CCK1 receptors limits the action of EA in the rVLM of rats in modulating reflex hypertension. (Supported by AHA 10POST4190125, NIH HL‐63313 and HL‐072125).

Non-Coding RNAs Regulating Morphine Function: With Emphasis on the In vivo and In vitro Functions of miR-190

Non-coding RNAs (ncRNAs), especially microRNAs, are reported to be involved in a variety of biological processes, including several processes related to drug addiction. It has been suggested that the biological functions of opioids, one typical type of addictive drugs, are regulated by ncRNAs. In the current review, we examine a variety of mechanisms through which ncRNAs could regulate μ-opioid receptor (OPRM1) activities and thereby contribute to the development of opioid addiction. Using miR-23b as an example, we present the possible ways in which ncRNA-mediated regulation of OPRM1 expression could impact opioid addiction. Using miR-190 as an example, we demonstrate the critical roles played by ncRNAs in the signal cascade from receptor to systemic responses, including the possible modulation of adult neurogenesis and in vivo contextual memory. After discussing the possible targets of ncRNAs involved in the development of opioid addiction, we summarize the mechanisms underlying the interaction between ncRNAs and opioid addiction and present suggestions for further study.

Interacting Effects of Trait Anger and Acute Anger Arousal on Pain

Elevated trait anger (TRANG; heightened propensity to experience anger) is associated with greater pain responsiveness, possibly via associations with deficient endogenous opioid analgesia. This study tested whether acute anger arousal moderates the impact of TRANG on endogenous opioid analgesia. Ninety-four chronic low back pain (LBP) participants and 85 healthy controls received opioid blockade (8 mg of naloxone) or placebo in a randomized, counterbalanced order in separate sessions. Participants were randomly assigned to undergo either a 5-minute anger recall interview (ARI) or a neutral control interview across both drug conditions. Immediately after the assigned interview, participants engaged sequentially in finger pressure and ischemic forearm pain tasks. Opioid blockade effects were derived (blockade minus placebo condition pain ratings) to index opioid antinociceptive function. Placebo condition TRANG by interview interactions (p values < .05) indicated that TRANG was hyperalgesic only in the context of acute anger arousal (ARI condition; p values < .05). Blockade effect analyses suggested that these hyperalgesic effects were related to deficient opioid analgesia. Significant TRANG by interview interactions (p values < .05) for both pain tasks indicated that elevated TRANG was associated with smaller blockade effects (less endogenous opioid analgesia) only in the ARI condition (p values < .05). Results for ischemic task visual analog scale intensity blockade effects suggested that associations between TRANG and impaired opioid function were most evident in LBP participants when experiencing anger (type by interview by TRANG interaction; p < .05). Results indicate that hyperalgesic effects of TRANG are most prominent when acute anger is aroused and suggest that endogenous opioid mechanisms contribute.

Hypothesizing Synergy between Acupuncture/ Auriculotherapy and Natural Activation of Mesolimbic Dopaminergic Pathways: Putative Natural Treatment Modalities for the Reduction of Drug Hunger and Relapse

Acupuncture is a very ancient form of healing which predates recorded history. The philosophy is rooted in the Taoist tradition which goes back over 8000 years. To date this practice although used world-wide to treat addictive behaviors has not been generally accepted or scientifically proven. There are however many positive reports in the literature in its effectiveness in reducing symptoms of withdrawal from alcohol, heroin and cocaine. In addition, due to known neuro-chemical mechanisms associated with acupuncture, especially its role in pain relief and endogenous opioid function, clinical benefits in reward dependence behaviors seem parsimonious. In this review article we are hypothesizing synergy between acupuncture/auriculotherapy and natural activation of mesolimbic dopaminergic pathways to reduce drug hunger and prevent relapse. Following a review of the literature involving both of these modalities the scientific and clinical community is encouraged to carry out translational research in large randomized double-blinded placebo controlled investigations coupling these two anti-craving treatment modalities.

Activation of κ opioid receptors increases intrinsic excitability of dentate gyrus granule cells

The dentate gyrus of the hippocampus is thought to control information flow into the rest of the hippocampus. Under pathological conditions, such as epilepsy, this protective feature is circumvented and uninhibited activity flows throughout the hippocampus. Many factors can modulate excitability of the dentate gyrus and ultimately, the hippocampus. It is therefore of critical importance to understand the mechanisms involved in regulating excitability in the dentate gyrus. Dynorphin, the endogenous ligand for the kappa (κ) opioid receptor (KOR), is thought to be involved in neuromodulation in the dentate gyrus. Both dynorphin and its receptor are widely expressed in the dentate gyrus and have been implicated in epilepsy and other complex behaviours such as stress-induced deficits in learning and stress-induced depression-like behaviours. Administration of KOR agonists can prevent both the behavioural and electroencephalographic measures of seizures in several different models of epilepsy. Antagonism of the KORs also prevents stress-induced behaviours. This evidence suggests the KORs as possible therapeutic targets for various pathological conditions. In addition, KOR agonists prevent the induction of LTP. Although there are several mechanisms through which dynorphin could mediate these effects, no studies to date investigated the effects of KOR activation on intrinsic membrane properties and cell excitability. We used whole-cell, patch-clamp recordings from acute mouse hippocampus slices to investigate the effect of KOR activation on dentate gyrus granule cell excitability. The agonist U69,593 (U6, 1 μM) resulted in a lower spike threshold, a decreased latency to first spike, an increased spike half-width, and an overall increase in spike number with current injections ranging from 15 to 45 pA. There was also a reduction in the interspike interval (ISI) both early and late in the spike train, with no change in membrane potential or input resistance. Preincubation of the slice with the selective KOR antagonist, nor-binalthorphimine (BNI, 1 μM) inhibited the effect of U6 on the latency to first spike and spike half-width suggesting that these effects are mediated through KORs. The inclusion of GDP-βS (1 mM) in the recording pipette prevented all of the U6 effects, suggesting that all effects are mediated via a G-protein-dependent mechanism. Inclusion of the A-type K+ current blocker, 4-aminopyridine (4-AP, 5 mM) in the pipette also antagonised the effects of U6. Kv4.2 is one of the channel α subunits thought to be responsible for carrying the A-type K+ current. Incubation of hippocampus slices with U6 resulted in a decrease in the Kv4.2 subunit protein at the cell surface. These results are consistent with an increase in cell excitability in response to KOR activation and may reflect new possibilities for additional opioid functions.

Endogenous opioid peptides in regulation of innate immunity cell functions

Endogenous opioid peptides comprise a group of bioregulatory factors involved in regulation of functional activity of various physiological systems of an organism. One of most important functions of endogenous opioids is their involvement in the interaction between cells of the nervous and immune systems. Summary data on the effects of opioid peptides on regulation of functions of innate immunity cells are presented.

A ligand-based 3D pharmacophore model for the μ opioid receptor: application to the morphinan class of opioids

Background Opioid receptors belong to the rhodopsin subclass within the superfamily of G protein-coupled receptors (GPCR), which are characterized by the presence of seven transmembrane (7TM) helices. They interact with morphine and related opioid alkaloids as well as with endogenous opioid peptides. There are three main types of opioid receptors (μ, δ, ), which are differently implicated in opioid function. Ligands specifically targeting each opioid receptor type are of high interest both as research tools and potential therapeutic agents. Activation of the μ opioid receptor produces many other effects, besides its main involvement in pain control, including immunomodulation, respiratory depression, constipation, tolerance and physical dependence. With the lack of an experimental 3D structure of the μ opioid receptor, discovery of 3D pharmacophores for the receptor that can explain the activity of a series of ligands represents an important approach in drug discovery.

Interactions of peripheral and central μ opioid systems during emotional stress

Background Numerous studies support an important contribution of endogenous opioid peptide systems in the mechanisms of emotional behavior. It is well known that the structure of opioid receptors (OR) and endogenous opioid peptides in the CNS and in the periphery is identical, but the central and peripheral functions of endogenous opioid systems are considered different, because the blood-brain barrier (BBB) generally prevents the entry of peptides into the brain. We hypothesize that the central and peripheral components of the endogenous opioid system function in close relationship, interacting with each other. The aim of this work was to study an influence of a peripheral administration of the μ opioid receptor ligands, which do not penetrate the BBB, on behavioral parameters as well as on extracellular levels of b-endorphin (BE) in the the cingulate cortex (CC) of rats during acute emotional stress.

Opioid‐modulating properties of the neuropeptide FF system

Opioid receptors are involved in the control of pain perception in the central nervous system together with endogenous neuropeptides, termed opioid-modulating peptides, participating in a homeostatic system. Neuropeptide FF (NPFF) and related peptides possess anti-opioid properties, the cellular mechanisms of which are still unclear. The purpose of this review is to detail the phenomenon of cross-talk taking place between opioid and NPFF systems at the in vivo pharmacological level and to propose cellular and molecular models of functioning. A better knowledge of the mechanisms underlying opioid-modulating properties of NPFF has potential therapeutic interest for the control of opioid functions, notably for alleviating pain and/or for the treatment of opioid abuse.

An Opioid Deficit in Borderline Personality Disorder: Self-Cutting, Substance Abuse, and Social Dysfunction

An Opioid Deficit in Borderline Personality Disorder: Self-Cutting, Substance Abuse, and Social Dysfunction

Opposite control of body temperature by NPFF1 and NPFF2 receptors in mice

Neuropeptide FF (NPFF) is a neurotransmitter known to modulate opioid functions. This study investigates the effects of RF9, a new antagonist of NPFF receptors, on the roles of NPFF1 and NPFF2 receptors in thermoregulation in mice. RF9 (10 nmol) injected into the third ventricle did not modify the body temperature as compared to saline, but it completely antagonized the hypothermic effects of 10 nmol NPVF, a NPFF1 selective agonist, as well as the hyperthermic actions of dNPA (5 nmol), a NPFF2 selective agonist. The use of a specific antagonist demonstrates here that central NPFF1 and NPFF2 receptors control in an opposite manner the body temperature in mice.

Dysregulation of Regional Endogenous Opioid Function in Borderline Personality Disorder

Borderline personality disorder is characterized by a lack of effective regulation of emotional responses. The authors investigated the role of the endogenous opioid system and mu-opioid receptors in emotion regulation in borderline personality disorder. Mu-opioid receptor availability in vivo (nondisplaceable binding potential, or BP(ND)) was measured with positron emission tomography and the selective radiotracer [(11)C]carfentanil during neutral and sustained sadness states in 18 unmedicated female patients with borderline personality disorder and 14 healthy female comparison subjects. Patients showed greater regional mu-opioid BP(ND) than did comparison subjects at baseline (neutral state) bilaterally in the orbitofrontal cortex, caudate, and nucleus accumbens and in the left amygdala, but lower BP(ND) in the posterior thalamus. Sadness induction was associated with greater reductions in BP(ND) (endogenous opioid system activation) in the patient group than in the comparison group in the pregenual anterior cingulate, left orbitofrontal cortex, left ventral pallidum, left amygdala, and left inferior temporal cortex. Patients showed evidence of endogenous opioid system deactivation in the left nucleus accumbens, the hypothalamus, and the right hippocampus/parahippocampus relative to comparison subjects. Correlations of baseline measures with the Dissociative Experiences Scale and endogenous opioid system activation with the Barratt Impulsiveness Scale did not remain significant after correction for multiple comparisons. Differences exist between patients with borderline personality disorder and comparison subjects in baseline in vivo mu-opioid receptor concentrations and in the endogenous opioid system response to a negative emotional challenge that can be related to some of the clinical characteristics of patients with borderline personality disorder. The regional network involved is implicated in the representation and regulation of emotion and stress responses.