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

Abstractµ-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.

Biphalin—A Potent Opioid Agonist—As a Panacea for Opioid System-Dependent Pathophysiological Diseases?

Biphalin, one of the opioid agonists, is a dimeric analog of enkephalin with a high affinity for opioid receptors. Opioid receptors are widespread in the central nervous system and in peripheral neuronal and non-neuronal tissues. Hence, these receptors and their agonists, which play an important role in pain blocking, may also be involved in the regulation of other physiological functions. Biphalin was designed and synthesized in 1982 by Lipkowski as an analgesic peptide. Extensive further research in various laboratories on the antinociceptive effects of biphalin has shown its excellent properties. It has been demonstrated that biphalin exhibits an analgesic effect in acute, neuropathic, and chronic animal pain models, and is 1000 times more potent than morphine when administered intrathecally. In the course of the broad conducted research devoted primarily to the antinociceptive effect of this compound, it has been found that biphalin may also potentially participate in the regulation of other opioid system-dependent functions. Nearly 40 years of research on the properties of biphalin have shown that it may play a beneficial role as an antiviral, antiproliferative, anti-inflammatory, and neuroprotective agent, and may also affect many physiological functions. This integral review analyzes the literature on the multidirectional biological effects of biphalin and its potential in the treatment of many opioid system-dependent pathophysiological diseases.

Depression, anxiety, and chronic fatigue symptoms in acute rheumatoid arthritis are associated with immune-inflammatory, autoimmune, endogenous opioid system and lactosylceramide signaling pathways: a nomothetic network approach

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disorder which affects the joints in the wrists, fingers, and knees. RA is often associated with depressive and anxiety symptoms as well as chronic fatigue syndrome (CFS)-like symptoms.AimTo examine the association between depressive symptoms (measured with the Beck Depression Inventory, BDI), anxiety (Hamilton Anxiety Rating Scale, HAMA), and CFS-like (Fibro-fatigue Scale) symptoms and immune-inflammatory, autoimmune, and endogenous opioid system (EOS) markers, and lactosylceramide in RA.MethodsSerum biomarkers were assayed in RA patients with (n=59) and without (n=59) increased psychopathology (PP) and 50 healthy controls.ResultsThere were highly significant correlations between the BDI, FF, and HAMA scores and severity of RA, as assessed with the DAS28-4, clinical and disease activity indices, the number of tenders and swollen joints, and patient and evaluator global assessment scores. A common latent vector (reflective model) could be extracted from the PP and RA-severity scales, which showed excellent psychometric properties. Partial least squares analysis showed that 69.7% of the variance in this common core underpinning PP and RA symptoms could be explained by the regression on immune-inflammatory pathways, rheumatoid factor and anti-citrullinated protein antibodies, CD17, and mu-opioid receptor levels.ConclusionsDepression, anxiety, and CFS-like symptoms due to RA are reflective manifestations of the phenome of RA and are mediated via the effects of the same immune-inflammatory, autoimmune, and EOS pathways and lactosylceramide that underpin the pathophysiology of RA. These PP symptoms are clinical manifestations of the pathophysiology of RA.

Depression, Anxiety, and Chronic Fatigue Symptoms in Acute Rheumatoid Arthritis are Associated with Immune-inflammatory, Autoimmune, Endogenous Opioid System and Lactosylceramide Signaling Pathways: A Nomothetic Network Approach

Background. Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disorder which affects the joints in the wrists, fingers, and knees. RA is often associated with depressive and anxiety symptoms as well as chronic fatigue syndrome (CFS)-like symptoms.Aim. To examine the association between depressive symptoms (measured with the Beck Depression Inventory, BDI), anxiety (Hamilton Anxiety Rating Scale, HAMA), and CFS-like (Fibro-fatigue Scale) symptoms and immune-inflammatory, autoimmune, and endogenous opioid system (EOS) markers, and lactosylceramide in RA. Methods. The serum biomarkers were assayed in fifty-nine RA and fifty-nine patients without increased psychopathology (PP) and fifty healthy controls.Results. There were highly significant correlations between the BDI, FF, and HAMA scores and severity of RA, as assessed with the DAS28-4, clinical and disease activity indices, the number of tenders and swollen joints, and patient and evaluator global assessment scores. A common latent vector (reflective model) could be extracted from the PP and RA-severity scales, which showed excellent psychometric properties. Partial least squares analysis showed that 69.7% of the variance in this common core underpinning PP and RA symptoms could be explained by the regression on immune-inflammatory pathways, rheumatoid factor, anti-citrullinated protein antibodies, CD17, and mu-opioid receptor levels. Conclusions. Depression, anxiety, and CFS-like symptoms due to RA are reflective manifestations of the phenome of RA and are mediated via the effects of the same immune-inflammatory, autoimmune, and EOS pathways and lactosylceramide that underpin the pathophysiology of RA. These PP symptoms are clinical manifestations of the pathophysiology of RA.

Multiple Sclerosis and the Endogenous Opioid System

Multiple sclerosis (MS) is an autoimmune disease characterized by chronic inflammation, neuronal degeneration and demyelinating lesions within the central nervous system. The mechanisms that underlie the pathogenesis and progression of MS are not fully known and current therapies have limited efficacy. Preclinical investigations using the murine experimental autoimmune encephalomyelitis (EAE) model of MS, as well as clinical observations in patients with MS, provide converging lines of evidence implicating the endogenous opioid system in the pathogenesis of this disease. In recent years, it has become increasingly clear that endogenous opioid peptides, binding μ- (MOR), κ- (KOR) and δ-opioid receptors (DOR), function as immunomodulatory molecules within both the immune and nervous systems. The endogenous opioid system is also well known to play a role in the development of chronic pain and negative affect, both of which are common comorbidities in MS. As such, dysregulation of the opioid system may be a mechanism that contributes to the pathogenesis of MS and associated symptoms. Here, we review the evidence for a connection between the endogenous opioid system and MS. We further explore the mechanisms by which opioidergic signaling might contribute to the pathophysiology and symptomatology of MS.

Do endogenous opioids mediate or fine-tune human pain relief?

We discuss how effects of different magnitudes from human opioid antagonist studies can be interpreted and how the results inform us on the role of the endogenous mu-opioid system for pain relief and other affective processes in humans. This is a commentary on Endogenous opioids contribute to the feeling of pain relief in humans by Sirucek et al, In Press, Pain.