PD98059 Influences Immune Factors and Enhances Opioid Analgesia in Model of Neuropathy.
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ABSTRACT:
SUBMITTER: Rojewska E
PROVIDER: S-EPMC4591269 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
Publications
PD98059 Influences Immune Factors and Enhances Opioid Analgesia in Model of Neuropathy.
Rojewska Ewelina E Popiolek-Barczyk Katarzyna K Kolosowska Natalia N Piotrowska Anna A Zychowska Magdalena M Makuch Wioletta W Przewlocka Barbara B Mika Joanna J
PloS one 20151001 10
Neuropathic pain treatment remains challenging due to ineffective therapy and resistance to opioid analgesia. Mitogen-activated protein kinase kinase (MAPKK) have been identified as the crucial regulators of pro- and antinociceptive factors. We used PD98059, an inhibitor of the MAPKK family members MEK1/2. The aim of study was to examine the influence of single and/or repeated PD98059 on nociception and opioid effectiveness in neuropathy. Moreover, we examined how PD98059 influences selected mem ...[more]
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Project description:IntroductionNegative affect, including anxiety and depression, is prevalent in chronic pain states such as osteoarthritis (OA) and associated with greater use of opioid analgesics, potentially contributing to present and future opioid crises.ObjectivesWe tested the hypothesis that the interaction between anxiety, chronic pain, and opioid use results from altered endogenous opioid function.MethodsA genetic model of negative affect, the Wistar-Kyoto (WKY) rat, was combined with intra-articular injection of monosodium iodoacetate (MIA; 1 mg) to mimic clinical presentation. Effects of systemic morphine (0.5-3.5 mg·kg-1) on pain behaviour and spinal nociceptive neuronal activity were compared in WKY and normo-anxiety Wistar rats 3 weeks after MIA injection. Endogenous opioid function was probed by the blockade of opioid receptors (0.1-1 mg·kg-1 systemic naloxone), quantification of plasma β-endorphin, and expression and phosphorylation of spinal mu-opioid receptor (MOR).ResultsMonosodium iodoacetate-treated WKY rats had enhanced OA-like pain, blunted morphine-induced analgesia, and greater mechanical hypersensitivity following systemic naloxone, compared with Wistar rats, and elevated plasma β-endorphin levels compared with saline-treated WKY controls. Increased MOR phosphorylation at the master site (serine residue 375) in the spinal cord dorsal horn of WKY rats with OA-like pain (P = 0.0312) indicated greater MOR desensitization.ConclusionsReduced clinical analgesic efficacy of morphine was recapitulated in a model of high anxiety and OA-like pain, in which endogenous opioid tone was altered, and MOR function attenuated, in the absence of previous exogenous opioid ligand exposure. These findings shed new light on the mechanisms underlying the increased opioid analgesic use in high anxiety patients with chronic pain.
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Project description:Increasing evidence has indicated that activated glial cells releasing nociceptive factors, such as interleukins and chemokines, are of key importance for neuropathic pain. Significant changes in the production of nociceptive factors are associated with the low effectiveness of opioids in neuropathic pain. Recently, it has been suggested that CCL2/CCR2 signaling is important for nociception. Here, we studied the time course changes in the mRNA/protein level of CD40/Iba-1, CCL2 and CCR2 in the spinal cord/dorsal root ganglia (DRG) in rats following chronic constriction injury (CCI) of the sciatic nerve. Moreover, we examined the influence of intrathecal preemptive and repeated (daily for 7 days) administration of RS504393, CCR2 antagonist, on pain-related behavior and the associated biochemical changes of some nociceptive factors as well as its influence on opioid effectiveness. We observed simultaneous upregulation of Iba-1, CCL2, CCR2 in the spinal cord on 7th day after CCI. Additionally, we demonstrated that repeated administration of RS504393 not only attenuated tactile/thermal hypersensitivity but also enhanced the analgesic properties of morphine and buprenorphine under neuropathy. Our results proof that repeated administration of RS504393 reduced the mRNA and/or protein levels of pronociceptive factors, such as IL-1beta, IL-18, IL-6 and inducible nitric oxide synthase (iNOS), and some of their receptors in the spinal cord and/or DRG. Furthermore, RS504393 elevated the spinal protein level of antinociceptive IL-1alpha and IL-18 binding protein. Our data provide new evidence that CCR2 is a promising target for diminishing neuropathic pain and enhancing the opioid analgesic effects.
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Project description:The ?-opioid receptor (MOR) agonist morphine is commonly used for pain management, but it has severe adverse effects and produces analgesic tolerance. Thus, alternative ways of stimulating MOR activity are needed. We found that MrgC11, a sensory neuron-specific G protein-coupled receptor, may form heteromeric complexes with MOR. Peptide-mediated activation of MrgC11 enhanced MOR recycling by inducing coendocytosis and sorting of MOR for membrane reinsertion. MrgC11 activation also inhibited the coupling of MOR to ?-arrestin-2 and enhanced the morphine-dependent inhibition of cAMP production. Intrathecal coadministration of a low dose of an MrgC agonist potentiated acute morphine analgesia and reduced chronic morphine tolerance in wild-type mice but not in Mrg-cluster knockout (Mrg KO) mice. BAM22, a bivalent agonist of MrgC and opioid receptors, enhanced the interaction between MrgC11 and MOR and produced stronger analgesia than did the individual monovalent agonists. Morphine-induced neuronal and pain inhibition was reduced in Mrg KO mice compared to that in wild-type mice. Our results uncover MrgC11-MOR interactions that lead to positive functional modulation of MOR. MrgC shares genetic homogeneity and functional similarity with human MrgX1. Thus, harnessing this positive modulation of MOR function by Mrg signaling may enhance morphine analgesia in a sensory neuron-specific fashion to limit central side effects.
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Project description:Labor initiates one of the most intensely painful episodes in a woman's life. Opioids are used to provide analgesia with substantial interindividual variability in efficacy. mu-Opioid receptor (muOR, OPRM1) genetic variants may explain differences in response to opioid analgesia. We hypothesized that OPRM1 304A/G polymorphism influences the median effective dose (ED(50)) of intrathecal fentanyl via combined spinal-epidural for labor analgesia. Nulliparous women were prospectively recruited around 35 weeks gestation (n=224), and genotyped for 304A/G polymorphism. Those requesting neuraxial labor analgesia were enrolled in one of the two double-blinded trials: up-down sequential allocation (SA, n=50) and a separate confirmatory random-dose allocation trial (RA, n=97). Effective analgesia from intrathecal fentanyl was defined by >or=60 min analgesia with verbal rating score <or=1 (scale 0-10) and was compared between mu OR 304A homozygotes (Group A) and women carrying at least one 304G allele (Group G). OPRM1 304G allele frequency f(-) was 0.18. Using SA, intrathecal fentanyl ED(50) was 26.8 microg (95% CI 22.7-30.9) in Group A and 17.7 microg (95% CI 13.4-21.9) in Group G (p<0.001; 304A homozygosity increased the ED(50) 1.5-fold). RA confirmed that 304A homozygosity significantly increases intrathecal fentanyl ED(50) (27.4 microg in Group A and 12.8 microg in Group G [p<0.002; 2.1-fold]). We demonstrate for the first time that the muOR 304G variant significantly reduces intrathecal fentanyl ED(50) for labor analgesia, suggesting women with the G variant may be more responsive to opioids and require less analgesic drugs. These findings for intrathecal fentanyl pharmacogenetics may have implications for patients receiving opioids in other settings.
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Project description:BACKGROUND:This is an updated version of the original Cochrane review published in Issue 4, 2006. Patients may control postoperative pain by self administration of intravenous opioids using devices designed for this purpose (patient controlled analgesia or PCA). A 1992 meta-analysis by Ballantyne et al found a strong patient preference for PCA over non-patient controlled analgesia, but disclosed no differences in analgesic consumption or length of postoperative hospital stay. Although Ballantyne's meta-analysis found that PCA did have a small but statistically significant benefit upon pain intensity, a 2001 review by Walder et al did not find statistically significant differences in pain intensity or pain relief between PCA and groups treated with non-patient controlled analgesia. OBJECTIVES:To evaluate the efficacy and safety of patient controlled intravenous opioid analgesia (termed PCA in this review) versus non-patient controlled opioid analgesia of as-needed opioid analgesia for postoperative pain relief. SEARCH METHODS:We ran the search for the previous review in November 2004. For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 12), MEDLINE (1966 to 28 January 2015), and EMBASE (1980 to 28 January 2015) for randomized controlled trials (RCTs) in any language, and reference lists of reviews and retrieved articles. SELECTION CRITERIA:We selected RCTs that assessed pain intensity as a primary or secondary outcome. These studies compared PCA without a continuous background infusion with non-patient controlled opioid analgesic regimens. We excluded studies that explicitly stated they involved patients with chronic pain. DATA COLLECTION AND ANALYSIS:Two review authors independently extracted data, which included demographic variables, type of surgery, interventions, efficacy, and adverse events. We graded each included study for methodological quality by assessing risk of bias and employed the GRADE approach to assess the overall quality of the evidence. We performed meta-analysis of outcomes that included pain intensity assessed by a 0 to 100 visual analog scale (VAS), opioid consumption, patient satisfaction, length of stay, and adverse events. MAIN RESULTS:Forty-nine studies with 1725 participants receiving PCA and 1687 participants assigned to a control group met the inclusion criteria. The original review included 55 studies with 2023 patients receiving PCA and 1838 patients assigned to a control group. There were fewer included studies in our updated review due to the revised exclusion criteria. For the primary outcome, participants receiving PCA had lower VAS pain intensity scores versus non-patient controlled analgesia over most time intervals, e.g., scores over 0 to 24 hours were nine points lower (95% confidence interval (CI) -13 to -5, moderate quality evidence) and over 0 to 48 hours were 10 points lower (95% CI -12 to -7, low quality evidence). Among the secondary outcomes, participants were more satisfied with PCA (81% versus 61%, P value = 0.002) and consumed higher amounts of opioids than controls (0 to 24 hours, 7 mg more of intravenous morphine equivalents, 95% CI 1 mg to 13 mg). Those receiving PCA had a higher incidence of pruritus (15% versus 8%, P value = 0.01) but had a similar incidence of other adverse events. There was no difference in the length of hospital stay. AUTHORS' CONCLUSIONS:Since the last version of this review, we have found new studies providing additional information. We reanalyzed the data but the results did not substantially alter any of our previously published conclusions. This review provides moderate to low quality evidence that PCA is an efficacious alternative to non-patient controlled systemic analgesia for postoperative pain control.
| S-EPMC7387354 | biostudies-literature
Project description:Opiates such as morphine and fentanyl, a major class of analgesics used in the clinical management of pain, exert their effects through the activation of opioid receptors. Opioids are among the most commonly prescribed and frequently abused drugs in the USA; however, the prolonged use of opiates often leads to the development of tolerance and addiction. Although blockade of opioid receptors with antagonists such as naltrexone and naloxone can lessen addictive impulses and facilitate recovery from overdose, systemic disruption of endogenous opioid receptor signalling through the use of these antagonistic drugs can have severe side effects. In the light of these challenges, current efforts have focused on identifying new therapeutic targets that selectively and specifically modulate opioid receptor signalling and function so as to achieve analgesia without the adverse effects associated with chronic opiate use. We have previously reported that opioid receptors interact with each other to form heteromeric complexes and that these interactions affect morphine signalling. Since chronic morphine administration leads to an enhanced level of these heteromers, these opioid receptor heteromeric complexes represent novel therapeutic targets for the treatment of pain and opiate addiction. In this review, we discuss the role of heteromeric opioid receptor complexes with a focus on mu opioid receptor (MOR) and delta opioid receptor (DOR) heteromers. We also highlight the evidence for altered pharmacological properties of opioid ligands and changes in ligand function resulting from the heteromer formation.
| S-EPMC3805500 | biostudies-literature
Project description:Translating pharmacogenetics to clinical practice has been particularly challenging in the context of pain, due to the complexity of this multifaceted phenotype and the overall subjective nature of pain perception and response to analgesia. Overall, numerous genes involved with the pharmacokinetics and dynamics of opioids response are candidate genes in the context of opioid analgesia. The clinical relevance of CYP2D6 genotyping to predict analgesic outcomes is still relatively unknown; the two extremes in CYP2D6 genotype (ultrarapid and poor metabolism) seem to predict pain response and/or adverse effects. Overall, the level of evidence linking genetic variability (CYP2D6 and CYP3A4) to oxycodone response and phenotype (altered biotransformation of oxycodone into oxymorphone and overall clearance of oxycodone and oxymorphone) is strong; however, there has been no randomized clinical trial on the benefits of genetic testing prior to oxycodone therapy. On the other hand, predicting the analgesic response to morphine based on pharmacogenetic testing is more complex; though there was hope that simple genetic testing would allow tailoring morphine doses to provide optimal analgesia, this is unlikely to occur. A variety of polymorphisms clearly influence pain perception and behavior in response to pain. However, the response to analgesics also differs depending on the pain modality and the potential for repeated noxious stimuli, the opioid prescribed, and even its route of administration.
| S-EPMC3513230 | biostudies-literature
Project description:ImportanceThe overprescription of opioids to surgical patients is recognized as an important factor contributing to the opioid crisis. However, the value of prescribing opioid analgesia (OA) vs opioid-free analgesia (OFA) after postoperative discharge remains uncertain.ObjectiveTo investigate the feasibility of conducting a full-scale randomized clinical trial (RCT) to assess the comparative effectiveness of OA vs OFA after outpatient general surgery.Design, setting, and participantsThis parallel, 2-group, assessor-blind, pragmatic pilot RCT was conducted from January 29 to September 3, 2020 (last follow-up on October 2, 2020). at 2 university-affiliated hospitals in Montreal, Quebec, Canada. Participants were adult patients (aged ≥18 years) undergoing outpatient abdominal (ie, cholecystectomy, appendectomy, or hernia repair) or breast (ie, partial or total mastectomy) general surgical procedures. Exclusion criteria were contraindications to drugs used in the trial, preoperative opioid use, conditions that could affect assessment of outcomes, and intraoperative or early complications requiring hospitalization.InterventionsPatients were randomized 1:1 to receive OA (around-the-clock nonopioids and opioids for breakthrough pain) or OFA (around-the-clock nonopioids with increasing doses and/or addition of nonopioid medications for breakthrough pain) after postoperative discharge.Main outcomes and measuresMain outcomes were a priori RCT feasibility criteria (ie, rates of surgeon agreement, patient eligibility, patient consent, treatment adherence, loss to follow-up, and missing follow-up data). Secondary outcomes included pain intensity and interference, analgesic intake, 30-day unplanned health care use, and adverse events. Between-group comparison of outcomes followed the intention-to-treat principle.ResultsA total of 15 surgeons were approached; all (100%; 95% CI, 78%-100%) agreed to have patients recruited and adhered to the study procedures. Rates of patient eligibility and consent were 73% (95% CI, 66%-78%) and 57% (95% CI, 49%-65%), respectively. Seventy-six patients were randomized (39 [51%] to OA and 37 [49%] to OFA) and included in the intention-to-treat analysis (mean [SD] age, 55.5 [14.5] years; 50 [66%] female); 40 (53%) underwent abdominal surgery, and 36 (47%) underwent breast surgery. Seventy-five patients (99%; 95% CI, 93%-100%) adhered to the allocated treatment; 1 patient randomly assigned to OFA received an opioid prescription. Seventeen patients (44%) randomly assigned to OA consumed opioids after discharge. Seventy-three patients (96%; 95% CI, 89%-99%) completed the 30-day follow-up. The rate of missing questionnaires was 37 of 3724 (1%; 95% CI, 0.7%-1.4%). All the a priori RCT feasibility criteria were fulfilled.Conclusions and relevanceThe findings of this pilot RCT support the feasibility of conducting a robust, full-scale RCT to inform evidence-based prescribing of analgesia after outpatient general surgery.Trial registrationClinicalTrials.gov Identifier: NCT04254679.
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