For decades the opioid receptors have been an attractive therapeutic target for the treatment of pain. Since the first discovery of enkephalin, approximately a dozen endogenous opioid peptides have been known to produce opioid activity and analgesia, but their therapeutics have been limited mainly due to low blood brain barrier penetration and poor resistance to proteolytic degradation. One versatile approach to overcome these drawbacks is the cyclization of linear peptides to cyclic peptides with constrained topographical structure. Compared to their linear parents, cyclic analogs exhibit better metabolic stability, lower offtarget toxicity, and improved bioavailability. Extensive structure-activity relationship studies have uncovered promising compounds for the treatment of pain as well as further elucidate structural elements required for selective opioid receptor activity. The benefits that come with employing cyclization can be further enhanced through the generation of polycyclic derivatives. Opioid ligands generally have a short peptide chain and thus the realm of polycyclic peptides has yet to be explored. In this review, a brief history of designing ligands for the opioid receptors, including classic linear and cyclic ligands, is discussed along with recent approaches and successes of cyclic peptide ligands for the receptors. Various scaffolds and approaches to improve bioavailability are elaborated and concluded with a discourse towards polycyclic peptides.

Bakgrund: Opioider är en viktig del inom behandling av postoperativ smärta. Det är viktigt att patienten erhåller adekvat information om opioder för att bespara patienten lidande och för att minimera riskabelt bruk. Syfte: Syftet var att beskriva patienters erfarenheter av att behandlas med opioider för postoperativ smärta. Metod: Studien utfördes som en allmän litteraturstudie med induktiv ansats. Litteraturstudien består av 17 vetenskapliga artiklar. Resultat: Resultatet genererade tre kategorier. Patienters fysiska erfarenheter innefattar patienters somatiska erfarenheter, hur de upplevde opioiders effekter och bieffekter. Patienters känslomässiga erfarenheter rymmer känslor som patienterna upplevde i samband med opioidbehandling och förutfattade meningar. Patienters erfarenheter av information omfattar vilken utbildning patienter hade erhållit av sjuksköterskan och vilka kunskapsbehov som upplevdes. Konklusion: Det var vanligt att patienterna upplevde biverkningar och uttryckte en oro över att uppleva biverkningar och att utveckla beroende. Patienterna hade även negativa föreställningar om opioider, vilket kunde resultera i att patienterna självmant reducerade sina doser eller slutade helt med sin behandling utan att rådfråga läkare. Bristfällig information om opioider resulterade i inadekvat smärtlindring. Sjuksköterskan är i behov av mer kunskap kring postoperativ opioidbehandling för att på så sätt kunna minska patienters oro, optimera smärthanteringen och minimera riskabelt handhavande av opioider. / Background: Opioids are an important part in the treatment of postoperative pain. It is important that patients receive adequate information regarding opioids to spare suffering and to minimize potentially dangerous use. Aim: The aim was to describe patients’ experiences of being treated with opioids for postoperative pain. Method: The method used was a literature review with an inductive approach, which consist of 17 scientific articles. Result: The result generated three categories. Patients’ physical experiences includes patients’ somatic experiences, how they experienced the opioids’ effects and side-effects. Patients’ emotional experiences contains emotions that patients experienced when being treated with opioids, as well as preconceptions. Patients’ experiences of information includes what education patients had received from the nurse and what knowledge they perceived to be lacking. Conclusion: It was common that patients experienced opioid-related side effects. Patients expressed fear of side effects and to become addicted. Patients’ negative views of opioids could result in poor prescription compliance. Either by reducing their dosages or quitting completely, without consulting a physician. Patients received inadequate information regarding opioids that resulted in insufficient pain treatment. The nurse is in need of more knowledge regarding postoperative opioid treatment, in order to reduce patients’ worry, optimise pain management and minimize unsafe use, storage and disposal of opioids.

The opioid epidemic is a public health crisis in the United States that impacts the lives of millions of people. There is a need for interventions aimed at minimizing opioid usage in clinical settings. The perioperative care period – consisting of the time before, during, and after surgery – is a time where interventions can be made in surgical and anesthesia practice to reduce the number of opioids used. Surgery and anesthesia are two areas where patients have traditionally been introduced to prescription opioids for the first time. Enhanced Recovery After Surgery pathways have been designed to integrate and improve surgical care for patients resulting in decreased length of stay in the hospital for surgical patients. Enhanced Recovery After Surgery pathways have also explored reducing opioid use during surgical care. Multimodal Analgesia and Opioid Free Anesthesia are two methods that have been researched and shown to be successful in limiting the perioperative use of opioids. Multimodal Analgesia and Opioid Free Anesthesia both reduce total perioperative opioid use and manage pain as effectively as opioids.

The midbrain periaqueductal gray matter (PAG) is an important brain region for the coordination of μ-opioid-induced pharmacological actions. The present study was designed to determine whether newly isolated μ-opioid peptide endomorphins can activate G proteins through μ-opioid receptors in the PAG by monitoring the binding to membranes of the non-hydrolyzable analog of GTP, guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPγS). An autoradiographic [35S]GTPγS binding study showed that both endomorphin-1 and -2 produced similar anatomical distributions of activated G proteins in the mouse midbrain region. In the mouse PAG, endomorphin-1 and -2 at concentrations from 0.001 to 10 μM increased [35S]GTPγS binding in a concentration-dependent manner and reached a maximal stimulation of 74.6 ± 3.8 and 72.3 ± 4.0%, respectively, at 10 μM. In contrast, the synthetic selective μ-opioid receptor agonist [D-Ala2,NHPhe4,Gly-ol]enkephalin (DAMGO) had a much greater efficacy and produced a 112.6 ± 5.1% increase of the maximal stimulation. The receptor specificity of endomorphin-stimulated [35S]GTPγS binding was verified by coincubating membranes with endomorphins in the presence of specific μ-, δ- or κ-opioid receptor antagonists. Coincubation with selective μ-opioid receptor antagonists β- funaltrexamine or D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 (CTOP) blocked both endomorphin-1 and-2-stimulated [35S]GTPγS binding. In contrast, neither δ- nor κ-opioid receptor antagonist had any effect on the [35S]GTPγS binding stimulated by either endomorphin-1 or -2. These findings indicate that both endomorphin-1 and -2 increase [35S]GTPγS binding by selectively stimulating μ-opioid receptors with intrinsic activity less than that of DAMGO and suggest that these new endogenous ligands might be partial agonists for μ-opioid receptors in the mouse PAG.

Pain is the universal symptom of illness and trauma. It affects people of all ages, cultures, and backgrounds, causing distress and suffering. Appearing in a plethora of diagnoses, almost all patients will experience some type of pain as a related symptom during their lifetime. The ubiquitous nature of pain renders it likely that a wide variety of healthcare providers will treat patients reporting pain in both the acute care and longitudinal settings. Many institutions and governing bodies in the medical sphere have emphasized the duty of the medical field to treat pain and thereby alleviate suffering. It is common for Emergency Medicine (EM) physicians to manage patients presenting to the Emergency Department (ED) in pain. Although these patients’ etiologies for their pain may differ, most will be experiencing pain from an acute insult. Emergency Medical Services (EMS) is the extension of EM into the prehospital setting. As such, EMS providers interact with many of the same patients experiencing acute pain. Despite the prevalence of pain and the importance of alleviating it, acute pain management has often been inadequate. Improving pain management should continue to be a high priority. Opioid analgesics have long been the standard of care for acute pain management. The first opiate, morphine, was isolated in the early 1800’s. Opioids are potent analgesics and are titratable to effect. However, they have a significant adverse effect profile. Among other adverse effects, opioids can cause hypotension and respiratory depression. In addition, the United States opioid epidemic has placed increased pressures on EMS and the entire healthcare profession to utilize opioid alternatives while continuing to improve the quality of acute pain management provided to patients. As a result, non-opioid analgesics have gained increased attention and use in EMS. They generally have fewer adverse effects than opioids and are not typically associated with a potential for addiction and abuse. However, the individual and subjective nature of the pain experience increases the difficulty of achieving improved analgesia. EMS providers must weigh these various factors and the complexity of the pain experience when determining the most appropriate treatment for acute pain. This review seeks to determine if non-opioid analgesics have potential for use as first line treatment by EMS over opioid analgesics, the standard of care for acute pain management. The purpose of this review of the current literature, especially comparison studies, is to investigate the common EMS analgesics: morphine, fentanyl, acetaminophen, ketorolac, ibuprofen, nitrous oxide, methoxyflurane, and ketamine. The findings are discussed in relation to four important outcome measures identified: effect on pain severity, rescue analgesic use, patient satisfaction, and the consideration of risks. Due to the paucity of research on this important topic, a general recommendation cannot be made for the use of non-opioid analgesics as first line treatment for acute pain management by EMS. However, this review provides several specific suggestions regarding the use of non-opioid analgesics as first line treatment by EMS. Applicability concerns are addressed, and a protocol is presented that EMS could use to adapt the findings to existing protocols.

No description available.

Pain is a significant health problem. Mu opioid receptor agonists are used clinically as analgesics, but their use is constrained by high abuse liability. Intracranial self-stimulation (ICSS) is a preclinical behavioral procedure that has been used to assess abuse potential of opioids, and drug-induced facilitation of ICSS is interpreted as an abuse-related effect. ICSS can also be used as a behavioral baseline to detect affective dimensions of pain. Specifically, pain-related depression of ICSS can model pain-related depression of behavior and mood, and drug-induced blockade of pain-related ICSS depression can serve as a measure of affective analgesia. This dissertation used mu agonists that vary in efficacy at the mu receptor (methadone> fentanyl> morphine> hydrocodone> buprenorphine> nalbuphine) and compared their effects on ICSS in the absence (phase one) or presence (phase 2) of pain. Adult male Sprague-Dawley rats were equipped with intracranial electrodes targeting the medial forebrain bundle and trained to lever press for brain stimulation. Different frequencies of stimulation maintained a frequency-dependent increase in ICSS rates, and permitted detection of both rate-increasing and rate-decreasing treatment effects. During phase 1, medium- and high-efficacy mu agonists produced initial rate-decreasing effects, followed by abuse-related rate-increasing effects at later time points. Repeated morphine administration produced tolerance to its own rate-decreasing effects, cross-tolerance to rate-decreasing effects of other mu agonists, and enhanced expression of rate-increasing effects. Low efficacy mu agonists only produced rate-increasing effects, which were enhanced after repeated morphine. These results suggest that previous opioid exposure increases expression of abuse-related facilitation of ICSS by mu agonists regardless of efficacy. During phase 2, intraperitoneal administration of lactic acid (1.8%) served as a noxious stimulus to depress ICSS. All mu agonists blocked acid-induced depression of ICSS at doses similar to those that facilitated ICSS in the absence of pain. A higher intensity noxious stimulus (5.6 % acid) produced further depression of ICSS and reduced the antinociceptive potency of both methadone and nalbuphine. Morphine antinociception was resistant to tolerance in the assay of acid-depressed ICSS. Overall, these results provide a basis for comparing determinants of abuse-related opioid effects in the absence of pain with their affective analgesic effects in the presence of pain.

No description available.

L’addiction ou dépendance aux substances psychoactives est une affection chronique, fréquente et grave, émaillée de rechutes et de périodes d’abstinence. Les études épidémiologiques montrent que l’abstinence aux opiacés est fortement associée à une prévalence accrue de la dépression. Nous résumons ici les principaux aspects cliniques de la dépendance aux opiacés et de la dépression, en détaillant leurs mécanismes physiopathologiques. Puis, nous présentons notre modèle d’abstinence aux opiacés chez la souris. Suite à un traitement morphinique chronique et au cours de l’abstinence apparaissent progressivement des comportements apparentés à la dépression. Ce traitement morphinique modifie profondément le fonctionnement du système sérotoninergique, notamment dans le noyau du raphé dorsal. De plus, les déficits comportementaux observés peuvent être prévenus par un traitement chronique par la fluoxétine, un antidépresseur ciblant ce système. Nous avons généralisé ce modèle à l’héroïne, un autre opiacé illicite. Nous avons révélé par des approches génétiques de délétion constitutive et conditionnelle les rôles distincts des 3 récepteurs opioïdes (mu, delta et kappa) lors de l’abstinence à l’héroïne. Enfin, nous avons initié une étude de caractérisation, à l’échelle de l’ensemble du génome, des adaptations transcriptomiques (ARN messagers et micro-ARN) dans le noyau du raphé dorsal au cours de l’abstinence à l’héroïne et du traitement antidépresseur. Ce travail devrait permettre d’améliorer notre compréhension des mécanismes neurobiologiques à l’œuvre dans la comorbidité entre dépendance aux opiacés et dépression et pourrait suggérer de nouvelles pistes thérapeutiques. / Addiction is a chronic, frequent and serious brain disease, with relapse alternating with abstinence periods. Epidemiological studies show that abstinence, notably from opiates, is strongly associated with depression.Here we present the main clinical aspects of opiate addiction and depression, and most recent advances in molecular pathophysiology of both disorders. Then, we present our mouse model of opiate abstinence. Following chronic morphine exposure, depressive-like behaviours progressively emerge. Morphine treatment profoundly disrupts serotonergic signalling, notably in the dorsal raphe nucleus. In addition, behavioural deficits can be prevented by chronic treatment with fluoxetine, an antidepressant targeting serotonergic neurons. We then generalized our mouse model to heroin, another major illicit opiate. Using constitutive and conditional knockout strategies, we documented distinct roles for all 3 opioid receptors (mu, delta and kappa) in heroin abstinence. Finally, we initiated a large-scale analysis of transcriptomic regulations (mRNA and micro-RNA) occurring in our model as a function of heroin abstinence and fluoxetine treatment.These studies should reveal an unforeseen contribution of the dorsal raphe nucleus to addiction. They should uncover new molecular mechanisms underlying depressive-like behaviors in mice during opiate abstinence and thus put forward new therapeutic targets in humans.

The binding of [³H]opioid ligands to homogenates prepared from the spinal cords of rat and other species has been studied. Similar numbers of sites were seen in all areas of the cord when measured in a rostrocaudal direction. There was found to be approximately 2 x higher density of sites in the dorsal half of the cord compared with the ventral half. Binding studies suggested a similar relative distribution of mu, delta and kappa sites in all areas of the cord. The results are discussed in relation to the reported distribution of opioid peptides. In the above study the kappa binding site was defined as the binding of [³H] unselective opioids in the presence of cold ligands to suppress binding to mu- and delta-sites. Competitive binding assays, however, suggested this site did not have the properties of a single homogeneous group. Approximately 50% of the apparent kappa binding was consistent with a classical kappa site. Saturated binding assays afforded Bmax values which suggested lower 'true' kappa site numbers than previously supposed, values which were confirmed using the kappa peptide' [³H]Dynorphin A-(1-9), and the kappa selective [³H]U-69593. Heterogeneity was also seen in other central nervous system tissues. The heterogeneous nature of the kappa site may be due to different sites, due to interactions at a non-opioid site or may represent different conformations of the same site. The second possibility was discounted since observed binding followed the cellular distribution of the plasma marker Na+/K+-ATPase was stereoselective for levorphanol over dextrorphan, and fully displaceable by naloxone. The third possibility was investigated by studying the role of Na+ and MG2+ ions, which are reported to affect receptor conformation in binding assays employing brain tissues. None of the results obtained suggested that conformational changes were responsible for the observed effects, although the experiments were not exhaustive.