A bifunctional-biased mu-opioid agonist–neuropeptide FF receptor antagonist as analgesic with improved acute and chronic side effects

Opioid analgesics, such as morphine, oxycodone, and fentanyl, are the cornerstones for treating moderate to severe pain. However, on chronic administration, their efficiency is limited by prominent side effects such as analgesic tolerance and dependence liability. Neuropeptide FF (NPFF) and its receptors (NPFF1R and NPFF2R) are recognized as an important pronociceptive system involved in opioid-induced hyperalgesia and analgesic tolerance. In this article, we report the design of multitarget peptidomimetic compounds that show high-affinity binding to the mu-opioid receptor (MOPr) and NPFFRs. In vitro characterization of these compounds led to identification of KGFF03 and KGFF09 as G-protein–biased MOPr agonists with full agonist or antagonist activity at NPFFRs, respectively. In agreement with their biased MOPr agonism, KGFF03/09 showed reduced respiratory depression in mice, as compared to the unbiased parent opioid agonist KGOP01. Chronic subcutaneous administration of KGOP01 and KGFF03 in mice rapidly induced hyperalgesia and analgesic tolerance, effects that were not observed on chronic treatment with KGFF09. This favorable profile was further confirmed in a model of persistent inflammatory pain. In addition, we showed that KGFF09 induced less physical dependence compared with KGOP01 and KGFF03. Altogether, our data establish that combining, within a single molecule, the G-protein–biased MOPr agonism and NPFFR antagonism have beneficial effects on both acute a...
Source: Pain - Category: Anesthesiology Tags: Research Paper Source Type: research

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DISCUSSION: ED utilization after outpatient hand surgery is low, with postoperative pain being the most common cause of an ED visit at all time points. Nearly 98% of patients presenting to the ED for postoperative pain are subsequently discharged home. LEVEL OF EVIDENCE: Level III, Retrospective Cohort. PMID: 31714419 [PubMed - as supplied by publisher]
Source: The Journal of the American Academy of Orthopaedic Surgeons - Category: Orthopaedics Tags: J Am Acad Orthop Surg Source Type: research
Placebo effects, a sum of different factors including non-specific effects, regression to the mean, natural history, and placebo responses, substantially contribute to clinical outcomes in diseases such as Parkinson's disease, depression, and immune function, as well as in acute and chronic pain conditions.10,33 Recent studies on placebo effects implicate the importance of informational context relative to medical treatments, most of which have no direct therapeutic effects on the body.42 One distinct feature of every therapeutic intervention is price, or treatment cost.
Source: The Journal of Pain - Category: Materials Science Authors: Tags: Original Reports Source Type: research
Ruona E Abstract Purpose: To study the use of Vibroacoustic treatment and an added self-care intervention for improving the functioning and ability to work of patients with chronic pain and potential comorbid depressive and anxious symptoms.Materials and methods: A mixed methods study with four single cases. Participants received bi-weekly Vibroacoustic practitioner-led treatment sessions for five weeks, followed by a one-month washout period without treatments. Then, participants conducted four self-care vibroacoustic sessions per week for five weeks, followed by another month-long washout period. Participants ke...
Source: Disability and Rehabilitation - Category: Rehabilitation Authors: Tags: Disabil Rehabil Source Type: research
Researchers at the University of Wisconsin-Madison have developed an injectable flexible electrode that can aid in neuromodulation therapy, potentially replacing more rigid electrodes that do not mesh well with soft tissues. The injectable material c...
Source: Medgadget - Category: Medical Devices Authors: Tags: Cardiology Materials Medicine Neurology Neurosurgery Pain Management Sports Medicine Source Type: blogs
The feeling of abandonment can span through all types of relationships and in this episode, we focus on friendships. Have you ever had a close friend abandon you or have you ever exited a friendship without notice? The emotions and actions surrounding the abandonment of friends can be complex and hurtful, but they are very real and can hurt deeply.  In this episode, Jackie recounts friendships that were very important to her and how she’s handling the loss of them. (Transcript Available Below) SUBSCRIBE &REVIEW About The Not Crazy Podcast Hosts Gabe Howard is an award-winning writer and speaker who live...
Source: World of Psychology - Category: Psychiatry & Psychology Authors: Tags: Communication Family Friends General Grief and Loss Not Crazy Podcast Relationships Source Type: blogs
(University of Wisconsin-Madison) By electrically stimulating nerves, neuromodulation therapies can reduce epileptic seizures, soothe chronic pain, and treat depression and a host of other health conditions without the use of conventional drugs like opioids. Now, University of Wisconsin-Madison biomedical engineers and their collaborators have made a significant advance that could dramatically reduce the cost of neuromodulation therapy, increase its reliability and make it much less invasive.
Source: EurekAlert! - Medicine and Health - Category: International Medicine & Public Health Source Type: news
CONCLUSIONS: This study supports the notion that the predictive power of the fear-avoidance model of pain is enhanced when individual differences in both pain-related vulnerability (e.g., catastrophizing) and pain-related protective resources (e.g., resilience) are considered. PMID: 31711106 [PubMed - as supplied by publisher]
Source: Annals of Behavioral Medicine - Category: Psychiatry & Psychology Authors: Tags: Ann Behav Med Source Type: research
ConclusionsA history of MST is common among older women veterans and associated with a range of medical and mental health diagnoses. These findings call attention to the need for additional research in this understudied population, and the importance of trauma-informed care approaches for women across the lifespan.
Source: Journal of General Internal Medicine - Category: Internal Medicine Source Type: research
Abstract BACKGROUND: Migraine is a diffuse and disabling disease. Its pathophysiology is complex and involves both central and peripheral dysfunctions. OBJECTIVE: This review will discuss the pathogenesis of migraine from the origin of the neuro-inflammatory theory, to the modern pathophysiological model and the latest therapies. METHODS: PUBMED and EMBASE (up to May 2019) were searched for: migraine, inflammation, immunomodulation. An additional search was carried out from the bibliography of previous review articles. RESULTS: Migraine was thought to be mainly a vascular disorder, according to the ...
Source: Current Pharmaceutical Design - Category: Drugs & Pharmacology Authors: Tags: Curr Pharm Des Source Type: research
DISCUSSION: The HiSQOL is a reliable and valid instrument to measure HS-specific HRQOL for clinical trials. PMID: 31705538 [PubMed - as supplied by publisher]
Source: The British Journal of Dermatology - Category: Dermatology Authors: Tags: Br J Dermatol Source Type: research
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