Imaging of opioid receptors in the central nervous system

In vivo functional imaging by means of positron emission tomography (PET) is the sole method for providing a quantitative measurement of μ-, κ and δ-opioid receptor-mediated signalling in the central nervous system. During the last two decades, measurements of changes to the regional brain opioidergic neuronal activation—mediated by endogenously produced opioid peptides, or exogenously administered opioid drugs—have been conducted in numerous chronic pain conditions, in epilepsy, as well as by stimulant- and opioidergic drugs. Although several PET-tracers have been used clinically for depiction and quantification of the opioid receptors changes, the underlying mechanisms for regulation of changes to the availability of opioid receptors are still unclear. After a presentation of the general signalling mechanisms of the opioid receptor system relevant for PET, a critical survey of the pharmacological properties of some currently available PET-tracers is presented. Clinical studies performed with different PET ligands are also reviewed and the compound-dependent findings are summarized. An outlook is given concluding with the tailoring of tracer properties, in order to facilitate for a selective addressment of dynamic changes to the availability of a single subclass, in combination with an optimization of the quantification framework are essentials for further progress in the field of in vivo opioid receptor imaging

Studies of dynorphin and cholecystokinin release in the rat spinal cord: implications for opioid action

Although much is now known of the cellular actions of exogenous opiate drugs and of endogenous opioid peptides, how these compounds modify interconnecting neuronal systems in the CNS is still poorly understood. The studies described in this thesis have addressed the latter by employing the antibody microprobe technique (Duggan A.W. and Hendry I.A., 1986, Neurosci. Letts. 68, 134-140) to investigate (a) the release of dynorphin A(l-8) in the spinal cord of the rat as inflammation develops in peripheral tissues, and (b) the release of cholecystokinin, a putative 'anti-opioid' neuropeptide, in the rat spinal cord following the administration of morphine.(a) A dramatic increase in the spinal synthesis of prodynorphin derived peptides has been observed when inflammation develops in peripheral tissues. The functional significance of this increased synthesis is unclear and there have been no reports of the stimuli needed to produce dynorphin release in vivo nor of possible controls of such release. Microprobes bearing immobilised antibodies to the dynorphin A(l-8) derivative of prodynorphin, were inserted into the lumbar spinal cord of urethane anaesthetised normal rats and those with a peripheral inflammation, to determine whether dynorphins are being tonically released and how release is altered by manipulating the inflamed tissues. In the absence of any active peripheral stimulus the antibody microprobes detected minimal amounts of immunoreactive (ir)-dynorphin A(l-8) in two areas (lamina I and laminae IV-V) in the dorsal horn of the spinal cord of normal rats. With the development of unilateral ankle inflammation over 3 to 5 days, following subcutaneous injections of Freund's complete adjuvant, this was extended to the ventral horn of both sides of the spinal cord. Lateral compression of the ankles of the normal animals did not release ir-dynorphin A(l-8) during the period of stimulation, but this neuropeptide was detected in the ventral horn following the stimulus. By contrast, compression of inflamed ankles produced elevated levels of ir-dynorphin A( 1 -8) during the period of stimulus application at three major sites in the spinal grey matter. The largest peak was in the deep dorsal horn/ upper ventral horn (laminae VI -VII), with further sites of significant release in the mid dorsal horn (laminae II-V) and the lower ventral horn. These levels persisted for at least one hour after the period of stimulation. At a cellular level dynorphins reduce transmitter release from nerve terminals, and hence the observation that ir-dynorphin A( 1 -8) is released in the ventral and deep dorsal horn in addition to the superficial dorsal horn of the rat by manipulation of inflamed tissues, implies that wide-spread spinal inhibitory controls of spinal neuronal firing are evoked by such stimuli. This may ultimately affect the perception of pain, but release in the ventral horn suggests an involvement in reducing motor responses to peripheral noxious stimuli.(b) Of all possible candidates at the spinal cord level, the 'anti-opioid' activity of cholecystokinin (CCK) has been well characterised. This peptide has also been proposed to play a role in the development of tolerance to but not dependence on opiate drugs. Although the hypothesis that stimulation of opioid receptors may trigger a progressive compensatory increase in the activity of CCK containing neurones at the spinal cord level has received some indirect support, this has not been thoroughly investigated. Conflicting data have been obtained from experiments which have examined the spinal cord content of CCK and spinal release of CCK following the administration of opioids. Microprobes bearing immobilised antibodies to CCK-8, were inserted into the lumbar spinal cord of urethane anaesthetised normal rats under both basal conditions and following acute opiate administration. In the absence of any active peripheral stimulus an extensive presence of ir-CCK was detected in normal (drug naive) rats with three main zones. The largest peak was in the mid to deep dorsal horn/ upper ventral horn (laminae III -VII), with further major sites in the superficial dorsal horn (lamina I-II) and the mid/ lower ventral horn. Morphine administered intravenously over two hours (total dose 25mg/ kg) failed to alter this basal presence of irCCK. Enhanced release however, was observed in areas of the ventral horn of rats treated acutely with morphine following lmg/ kg injections of naloxone. It is proposed that the occupation of opioid receptors by morphine triggers the increased synthesis of CCK and predicted that following the development of tolerance to morphine, enhanced CCK release will be observed in the absence of naloxone administration

Morphine modulation of pain processing in medial and lateral pain pathways

<p>Abstract</p> <p>Background</p> <p>Despite the wide-spread use of morphine and related opioid agonists in clinic and their powerful analgesic effects, our understanding of the neural mechanisms underlying opioid analgesia at supraspinal levels is quite limited. The present study was designed to investigate the modulative effect of morphine on nociceptive processing in the medial and lateral pain pathways using a multiple single-unit recording technique. Pain evoked neuronal activities were simultaneously recorded from the primary somatosensory cortex (SI), ventral posterolateral thalamus (VPL), anterior cingulate cortex (ACC), and medial dorsal thalamus (MD) with eight-wire microelectrode arrays in awake rats.</p> <p>Results</p> <p>The results showed that the noxious heat evoked responses of single neurons in all of the four areas were depressed after systemic injection of 5 mg/kg morphine. The depressive effects of morphine included (i) decreasing the neuronal response magnitude; (ii) reducing the fraction of responding neurons, and (iii) shortening the response duration. In addition, the capability of cortical and thalamic neural ensembles to discriminate noxious from innocuous stimuli was decreased by morphine within both pain pathways. Meanwhile, morphine suppressed the pain-evoked changes in the information flow from medial to lateral pathway and from cortex to thalamus. These effects were completely blocked by pre-treatment with the opiate receptor antagonist naloxone.</p> <p>Conclusion</p> <p>These results suggest that morphine exerts analgesic effects through suppressing both sensory and affective dimensions of pain.</p

Evaluation of the analgesic effect of 4-anilidopiperidine scaffold containing ureas and carbamates

Fentanyl is a powerful opiate analgesic typically used for the treatment of severe and chronic pain, but its prescription is strongly limited by the well-documented side-effects. Different approaches have been applied to develop strong analgesic drugs with reduced pharmacologic side-effects. One of the most promising is the design of multitarget drugs. In this paper we report the synthesis, characterization and biological evaluation of twelve new 4-anilidopiperidine (fentanyl analogues). In vivo hot-Plate test, shows a moderate antinociceptive activity for compounds OMDM585 and OMDM586, despite the weak binding affinity on both μ and δ-opioid receptors. A strong inverse agonist activity in the GTP-binding assay was revealed suggesting the involvement of alternative systems in the brain. Fatty acid amide hydrolase inhibition was evaluated, together with binding assays of cannabinoid receptors. We can conclude that compounds OMDM585 and 586 are capable to elicit antinociception due to their multitarget activity on different systems involved in pain modulation. © 2016 Informa UK Limited, trading as Taylor &amp; Francis Group

Analysis of the Genetic and Neurological Components of Opioid Addiction, with Public Health Perspectives of the Opioid Epidemic in the United States of America

Opioid addiction has reached epidemic levels around the world, with over-prescription of opioid pain relievers being an often-cited reason for the epidemic in the USA. This project looks at opioid addiction from three perspectives: a review of literature dealing with the neural pathways involved in opioid use and addiction; the underlying genetic differences that can increase the risk of opioid use disorder; and an overview of the public health aspects of the epidemic. The paper will conclude with a review of current and new treatments based upon a growing neurobiological and molecular understanding of opioid use disorder

The opioid systems and the role of glial cells in the effects of opioids

Understanding of the molecular mechanisms in the opioid systems in chronic pain should produce new, more effective methods of the pharmacotherapy of pain. Pharmacological suppression of glial activation in combination with morphine, methadone, fentanyl and buprenorphine may be an important aspect of pain therapy. Long-term use of the classical opioid analgesics in patients with chronic pain processes results in tolerance, and the search of new treatment strategies based on the recognised mechanisms of pain is an important clinical and scientific issue.Understanding of the molecular mechanisms in the opioid systems in chronic pain should produce new, more effective methods of the pharmacotherapy of pain. Pharmacological suppression of glial activation in combination with morphine, methadone, fentanyl and buprenorphine may be an important aspect of pain therapy. Long-term use of the classical opioid analgesics in patients with chronic pain processes results in tolerance, and the search of new treatment strategies based on the recognised mechanisms of pain is an important clinical and scientific issue

The aetiology of social deficits within mental health disorders:The role of the immune system and endogenous opioids

The American National Institute for Mental Health (NIMH) has put out a set of research goals that include a long-term plan to identify more reliable endogenous explanations for a wide variety of mental health disorders (Insel, 2013). In response to this, we have identified a major symptom that underlies multiple mental health disorders – social bonding dysfunction. We suggest that endogenous opioid abnormalities can lead to altered social bonding, which is a symptom of various mental health disorders, including depression, schizophrenia and ASD. This article first outlines how endogenous opioids play a role in social bonding. Then we show their association with the body’s inflammation immune function, and review recent literature linking inflammation to mental health ‘immunophenotypes’. We finish by explaining how these immunophenotypes may be caused by alterations in the endogenous opioid system. This is the first overview of the role of inflammation across multiple disorders where we provide a biochemical explanation for why immunophenotypes might exist across diagnoses. We propose a novel mechanism of how the immune system may be causing ‘sickness-type’ behaviours (fatigue, appetite change, social withdrawal and inhibited motivation) in those who have these immunophenotypes. We hope that this novel aetiology can be used as a basis for future research in mental health

Developing a Brain‐Based, Non‐Invasive Treatment for Pain

Chronic pain cost society more than $500 billion each year and contributes to the ongoing opioid overdose crisis. Substantial risks and low efficacy are associated with opiate usage for chronic pain. This dissertation seeks to fill the urgent need for a new pain treatment using a neural-circuit based approach in healthy controls and chronic pain patients. First, we performed a single-blind study examining the causal effects of transcranial magnetic stimulation (TMS), compared to a well-matched control condition. Using interleaved TMS/fMRI we explored brain activation in response to dorsolateral prefrontal cortex (DLPFC) stimulation in 20 healthy controls. This study tested the hypothesis that the TMS evoked responses would be in frontostriatal locations. Consistent with this hypothesis active TMS, compared to the control, led to significantly greater activity in the caudate, thalamus and anterior cingulate cortex (ACC). Building on these findings, we developed a single-blind, sham-controlled study examining two TMS strategies for analgesia in 45 healthy controls. We completed an fMRI thermal pain paradigm before and after modulatory repetitive TMS at either the DLPFC or the medial prefrontal cortex (MPFC). Despite a role in pain processing, the MPFC has not yet been explored as a target for analgesia. Only MPFC stimulation significantly improved behavioral pain measures. These effects were associated with increased motor and parietal cortex activity during the pain task. We then supplement these findings by testing the hypothesis that chronic pain patients who use opioids (n=14) would have elevated brain responses to thermal pain relative to healthy controls (n=14). Despite indistinguishable self-report measures, we found increased brain activity in the ACC and sensory areas in patients which were positively correlated with opioid dose. We conclude by evaluating the feasibility of these approaches in chronic pain patients, reporting preliminary findings from a pilot study examining the two treatment strategies tested previously in controls. Collectively, our findings support a circuits-first approach to pain treatment. Though MPFC stimulation was effective in reducing pain in healthy controls, further work is required to confirm these results in a chronic pain population, as chronic pain and opioid usage alter how the brain processes the pain experience