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Analgesic Properties of Opioid/NK1 Multitarget Ligands with Distinct in Vitro Profiles in Naive and Chronic Constriction Injury Mice.

ABSTRACT: The lower efficacy of opioids in neuropathic pain may be due to the increased activity of pronociceptive systems such as substance P. We present evidence to support this hypothesis in this work from the spinal cord in a neuropathic pain model in mice. Biochemical analysis confirmed the elevated mRNA and protein level of pronociceptive substance P, the major endogenous ligand of the neurokinin-1 (NK1) receptor, in the lumbar spinal cord of chronic constriction injury (CCI)-mice. To improve opioid efficacy in neuropathic pain, novel compounds containing opioid agonist and neurokinin 1 (NK1) receptor antagonist pharmacophores were designed. Structure-activity studies were performed on opioid agonist/NK1 receptor antagonist hybrid peptides by modification of the C-terminal amide substituents. All compounds were evaluated for their affinity and in vitro activity at the mu opioid (MOP) and delta opioid (DOP) receptors, and for their affinity and antagonist activity at the NK1 receptor. On the basis of their in vitro profiles, the analgesic properties of two new bifunctional hybrids were evaluated in naive and CCI-mice, representing models for acute and neuropathic pain, respectively. The compounds were administered to the spinal cord by lumbar puncture. In naive mice, the single pharmacophore opioid parent compounds provided better analgesic results, as compared to the hybrids (max 70% MPE), raising the acute pain threshold close to 100% MPE. On the other hand, the opioid parents gave poor analgesic effects under neuropathic pain conditions, while the best hybrid delivered robust (close to 100% MPE) and long lasting alleviation of both tactile and thermal hypersensitivity. The results presented emphasize the potential of opioid/NK1 hybrids in view of analgesia under nerve injury conditions.

SUBMITTER: Starnowska J

PROVIDER: S-EPMC5647227 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Analgesic Properties of Opioid/NK1 Multitarget Ligands with Distinct in Vitro Profiles in Naive and Chronic Constriction Injury Mice.

Starnowska Joanna J Costante Roberto R Guillemyn Karel K Popiolek-Barczyk Katarzyna K Chung Nga N NN Lemieux Carole C Keresztes Attila A Van Duppen Joost J Mollica Adriano A Streicher John J Vanden Broeck Jozef J Schiller Peter W PW Tourwé Dirk D Mika Joanna J Ballet Steven S Przewlocka Barbara B

ACS chemical neuroscience 20170726 10

The lower efficacy of opioids in neuropathic pain may be due to the increased activity of pronociceptive systems such as substance P. We present evidence to support this hypothesis in this work from the spinal cord in a neuropathic pain model in mice. Biochemical analysis confirmed the elevated mRNA and protein level of pronociceptive substance P, the major endogenous ligand of the neurokinin-1 (NK1) receptor, in the lumbar spinal cord of chronic constriction injury (CCI)-mice. To improve opioid ...[more]

PMID: 28699350

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Project description:BackgroundNon-opioid analgesics are prescribed in combination with opioids among patients with long bone fracture to reduce opioid prescribing needs, yet evidence is limited on whether they reduce the risk of serious opioid-related events (SOREs). We compared the risk of SOREs among hospitalized patients with long bone fracture discharged with filled opioid prescriptions, with and without non-opioid analgesics.DesignWe identified a retrospective cohort of analgesic-naïve adult patients with a long bone fracture hospitalization using the Merative MarketScan Commercial Database (2013-2020). The exposure was opioid and non-opioid analgesic (gabapentinoids, muscle relaxants, non-steroidal anti-inflammatory drugs, acetaminophen) prescriptions filled in the 3 days before through 42 days after discharge. The outcome was the development of new persistent opioid use or opioid use disorder during follow-up (day 43 through day 408 after discharge). We used Cox proportional hazards regression with inverse probability of treatment weighting with overlap trimming to compare outcomes among those that filled an opioid and a non-opioid analgesic to those that filled only an opioid analgesic. In secondary analyses, we used separate models to compare those that filled a prescription for each specific non-opioid analgesic type with opioids to those that filled only opioids.ResultsOf 29 489 patients, most filled an opioid prescription alone (58.4%) or an opioid and non-opioid (22.0%). In the weighted proportional hazards regression model accounting for relevant covariates and total MME, filling both a non-opioid analgesic and an opioid analgesic was associated with 1.63 times increased risk of SOREs compared with filling an opioid analgesic only (95% CI 1.41 to 1.89). Filling a gabapentin prescription in combination with an opioid was associated with an increased risk of SOREs compared with those that filled an opioid only (adjusted HR: 1.84 (95% CI1.48 to 2.27)).ConclusionsFilling a non-opioid analgesic in combination with an opioid was associated with an increased risk of SOREs after long bone fracture.Level of evidenceLevel III, prognostic/epidemiological.Study typeRetrospective cohort study.

Dataset Information

Analgesic Properties of Opioid/NK1 Multitarget Ligands with Distinct in Vitro Profiles in Naive and Chronic Constriction Injury Mice.

Publications

Analgesic Properties of Opioid/NK1 Multitarget Ligands with Distinct in Vitro Profiles in Naive and Chronic Constriction Injury Mice.

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