Pharmacokinetics Of Morphine Research Articles

Epidural methadone and morphine pharmacokinetics and clinical effects in healthy volunteers: A randomized, crossover-design trial.

Epidural opioids can provide effective analgesia for acute postoperative pain. Due to its unique physicochemical properties and long systemic elimination half-life, epidural methadone may provide lasting analgesia with minimal adverse effects; however, human studies are lacking. The aim of the study was to test the hypothesis that epidural methadone would exhibit greater segmental analgesia (analgesia at the dermatome of injection vs. distant dermatomes) than epidural morphine. In a prospective, randomized, double-blinded, crossover study, thirteen healthy volunteers received a 4-mg epidural bolus of methadone or morphine at L3-L4 and underwent repeated assessment of dermatomal heat pain tolerance and pressure pain threshold at lumbar (L3) and trigeminal (V2) dermatomes, pupil diameter, respiratory parameters and venous opioid concentration for 24 h. The primary outcome was selective (lumbar vs. trigeminal) segmental analgesia for heat pain, as a marker of a spinal analgesic mechanism. The degree of segmental analgesia to heat pain tolerance was not different between morphine and methadone (P =.09), although morphine (P =.0009) but not methadone (P =.81) produced significant analgesia to heat pain at the lumbar vs. trigeminal dermatome over 0-12 h. Morphine overall provided longer lasting analgesia to heat pain vs. methadone (24 vs. 2 h, respectively). Morphine elicited greater systemic effects, including miosis (P =.009) and opioid-related adverse effects (P =.002). These results suggest that, with equal epidural doses, both methadone and morphine produced analgesia and methadone did not produce greater segmental effects than morphine. Epidural methadone provided a more favourable adverse effect profile.

Physiologically based pharmacokinetic modeling to predict the pharmacokinetics of codeine in different CYP2D6 phenotypes.

Codeine, a prodrug used as an opioid agonist, is metabolized to the active product morphine by CYP2D6. This study aimed to establish physiologically based pharmacokinetic (PBPK) models of codeine and morphine and explore the influence of CYP2D6 genetic polymorphisms on the pharmacokinetics of codeine and morphine. An initial PBPK modeling of codeine in healthy adults was established using PK-Sim® software and subsequently extrapolated to CYP2D6 phenotype-related PBPK modeling based on the turnover frequency (Kcat) of CYP2D6 for different phenotype populations (UM, EM, IM, and PM). The mean fold error (MFE) and geometric mean fold error (GMFE) methods were used to compare the differences between the predicted and observed values of the pharmacokinetic parameters to evaluate the accuracy of PBPK modeling. The validated models were then used to support dose safety for different CYP2D6 phenotypes. The developed and validated CYP2D6 phenotype-related PBPK model successfully predicted codeine and morphine dispositions in different CYP2D6 phenotypes. Compared with EMs, the predicted AUC0-∞ value of morphine was 98.6% lower in PMs, 60.84% lower in IMs, and 73.43% higher in UMs. Morphine plasma exposure in IMs administered 80mg of codeine was roughly comparable to that in EMs administered 30mg of codeine. CYP2D6 UMs may start dose titration to achieve an optimal individual regimen and avoid a single dose of over 20mg. Codeine should not be used in PMs for pain relief, considering its insufficient efficacy. PBPK modeling can be applied to explore the dosing safety of codeine and can be helpful in predicting the effect of CYP2D6 genetic polymorphisms on drug-drug interactions (DDIs) with codeine in the future.

PBPK-PD model for predicting morphine pharmacokinetics, CNS effects and naloxone antagonism in humans.

Morphine and morphine-6-glucuronide (M6G) produce central nervous system (CNS) effects by activating mu-opioid receptors, while naloxone is used mainly for the reversal of opioid overdose, specifically for the fatal complication of respiratory depression, but also for alleviating opioid-induced side effects. In this study we developed a physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model to simultaneously predict pharmacokinetics and CNS effects (miosis, respiratory depression and analgesia) of morphine as well as antagonistic effects of naloxone against morphine. The pharmacokinetic and pharmacodynamic parameters were obtained from in vitro data, in silico, or animals. Pharmacokinetic and pharmacodynamic simulations were conducted using 39 and 36 clinical reports, respectively. The pharmacokinetics of morphine and M6G following oral or intravenous administration were simulated, and the PBPK-PD model was validated using clinical observations. The Emax model correlated CNS effects with free concentrations of morphine and M6G in brain parenchyma. The predicted CNS effects were compared with observations. Most clinical observations fell within the 5th-95th percentiles of simulations based on 1000 virtual individuals. Most of the simulated area under the concentration-time curve or peak concentrations also fell within 0.5-2-fold of observations. The contribution of morphine to CNS effects following intravenous or oral administration was larger than that of M6G. Pharmacokinetics and antagonistic effects of naloxone on CNS effects were also successfully predicted using the developed PBPK-PD model. In conclusion, the pharmacokinetics and pharmacodynamics of morphine and M6G, antagonistic effects of naloxone against morphine-induced CNS effects may be successfully predicted using the developed PBPK-PD model based on the parameters derived from in vitro, in silico, or animal studies.

Developing mathematical models to compare and analyse the pharmacokinetics of morphine and fentanyl.

The two-compartment model is generally used in pharmacokinetics to illustrate the distribution and excretion of drugs. In this study, we evaluated the distribution patterns of morphine and fentanyl by using a two-compartment model. Using numeric analysis techniques, non-linear ordinary differential equations were used to mathematically analyse drug distribution, transition, and concentration in the body compartments. Math Works, Inc., MATLAB, version 2023a, a programming tool, was used to characterise the impact of initial concentration and rate constants on the kinetics of the drug. For a definite therapeutic concentration of morphine and fentanyl in blood, pharmacokinetic characteristics were plotted. The study results showed the time taken by morphine and fentanyl to reach a target concentration in the blood that is sufficient to generate the preferred therapeutic effects. The mathematical models comparing morphine and fentanyl pharmacokinetics showed that fentanyl reached the target therapeutic concentration 125 minutes earlier than morphine and was metabolised and removed from the body more rapidly (44 minutes earlier than morphine). These comparative mathematical models on morphine and fentanyl enable the determination of drug dosages and understanding of drug efficacy that facilitates optimising dosing regimens. The right choice between them can be made based on the time to reach the target therapeutic concentration in the blood, elimination time, severity of pain, and patient characteristics.

Morphine pharmacokinetics and opioid transporter expression at the blood-retina barrier of male and female mice.

Opioids are effective analgesics for treating moderate to severe pain, however, their use must be weighed against their dangerous side effects. Investigations into opioid pharmacokinetics provide crucial information regarding both on- and off-target drug effects. Our recent work showed that morphine deposits and accumulates in the mouse retina at higher concentrations than in the brain upon chronic systemic exposure. We also found reduced retinal expression of P-glycoprotein (P-gp), a major opioid extruder at the blood-brain barrier (BBB). Here, we systematically interrogated the expression of three putative opioid transporters at the blood-retina barrier (BRB): P-gp, breast cancer resistance protein (Bcrp) and multidrug resistance protein 2 (Mrp2). Using immunohistochemistry, we found robust expression of P-gp and Bcrp, but not Mrp2, at the inner BRB of the mouse retina. Previous studies have suggested that P-gp expression may be regulated by sex hormones. However, upon acute morphine treatment we found no sex differences in morphine deposition levels in the retina or brain, nor on transporter expression in the retinas of males and females with a high or low estrogen:progesterone ratio. Importantly, we found that P-gp, but not Bcrp, expression significantly correlated with morphine concentration in the retina, suggesting P-gp is the predominant opioid transporter at the BRB. In addition, fluorescence extravasation studies revealed that chronic morphine treatment did not alter the permeability of either the BBB or BRB. Together, these data suggest that reduced P-gp expression mediates retinal morphine accumulation upon systemic delivery, and in turn, potential effects on circadian photoentrainment.

Does nonlinear blood-brain barrier transport matter for (lower) morphine dosing strategies?

Morphine blood-brain barrier (BBB) transport is governed by passive diffusion, active efflux and saturable active influx. This may result in nonlinear plasma concentration-dependent brain extracellular fluid (brainECF) pharmacokinetics of morphine. In this study, we aim to evaluate the impact of nonlinear BBB transport on brainECF pharmacokinetics of morphine and its metabolites for different dosing strategies using a physiologically based pharmacokinetic simulation study. We extended the human physiologically based pharmacokinetic LeiCNS-PK3.0, model with equations for nonlinear BBB transport of morphine. Simulations for brainECF pharmacokinetics were performed for various dosing strategies: intravenous (IV), oral immediate (IR) and extended release (ER) with dose range of 0.25–150 mg and dosing frequencies of 1–6 times daily. The impact of nonlinear BBB transport on morphine CNS pharmacokinetics was evaluated by quantifying (i) the relative brainECF to plasma exposure (AUCu,brainECF/AUCu,plasma) and (ii) the impact on the peak-to-trough ratio (PTR) of concentration-time profiles in brainECF and plasma. We found that the relative morphine exposure and PTRs are dose dependent for the evaluated dose range. The highest relative morphine exposure value of 1.4 was found for once daily 0.25 mg ER and lowest of 0.1 for 6-daily 150 mg IV dosing. At lower doses the PTRs were smaller and increased with increasing dose and stabilized at higher doses independent of dosing frequency. Relative peak concentrations of morphine in relation to its metabolites changed with increasing dose. We conclude that nonlinearity of morphine BBB transport affects the relative brainECF exposure and the fluctuation of morphine and its metabolites mainly at lower dosing regimens.

Pharmacokinetics of morphine and plasma concentrations of morphine-6-glucuronide after a single intravenous and intramuscular administration in the cow.

Introduction: This study aimed to determine morphine pharmacokinetics and morphine-6-glucuronide production quantification following intravenous (IV) and intramuscular (IM) administration in cattle.

In Silico Modeling for Ex Vivo Placental Transfer of Morphine.

Morphine may be administered in pregnant women as an analgesic agent. The transplacental pharmacokinetics (PK) of morphine varies during pregnancy because of physiological and metabolic changes. In this work, we use a multi‐compartment model to simulate ex vivo human placental transfer studies of morphine. The computational model is based on a recently published model for metformin with both passive and active transport kinetics. Modifications were made to incorporate morphine‐specific transfer parameters. Parameters for the PK models were determined via the nonlinear regression method. In addition, the Latin hypercube sampling (LHS) method was used for the global parameter analysis of the model. Simulation results show good agreement between the model and observed fetal and maternal morphine concentrations. In addition, the lower efflux of morphine from fetal to maternal plasma reflects reduced P‐glycoprotein (P‐gp) transport as pregnancy progresses, which leads to slower clearance of morphine in the maternal plasma. The LHS analysis also indicates the more significant roles played by the passive diffusion parameters than the active transport parameter on the fetal/maternal morphine concentrations. In conclusion, we used an in silico model to investigate the transplacental properties of morphine and to predict the in vivo transplacental properties of morphine when PK parameters change.

Morphine Accumulates in the Retina Following Chronic Systemic Administration.

Opioid transport into the central nervous system is crucial for the analgesic efficacy of opioid drugs. Thus, the pharmacokinetics of opioid analgesics such as morphine have been extensively studied in systemic circulation and the brain. While opioid metabolites are routinely detected in the vitreous fluid of the eye during postmortem toxicological analyses, the pharmacokinetics of morphine within the retina of the eye remains largely unexplored. In this study, we measured morphine in mouse retina following systemic exposure. We showed that morphine deposits and persists in the retina long after levels have dropped in the serum. Moreover, we found that morphine concentrations (ng/mg tissue) in the retina exceeded brain morphine concentrations at all time points tested. Perhaps most intriguingly, these data indicate that following chronic systemic exposure, morphine accumulates in the retina, but not in the brain or serum. These results suggest that morphine can accumulate in the retina following chronic use, which could contribute to the deleterious effects of chronic opioid use on both image-forming and non-image-forming visual functions.

Effects of Obstructive Sleep Apnea and Obesity on Morphine Pharmacokinetics in Children: Erratum.

Effects of Obstructive Sleep Apnea and Obesity on Morphine Pharmacokinetics in Children: Erratum.

No significant influence of OCT1 genotypes on the pharmacokinetics of morphine in adult surgical patients.

We investigated the impact of genetic variants in OCT1 (SLC22A1) on morphine, morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G) pharmacokinetics in adult patients scheduled for major surgery. Blood samples were taken before and 5, 10, 15, 30, 45, 60 and 90 min after a bolus of morphine (0.15 mg/kg). Patients were genotyped for the genetic variants (rs12208357, rs34059508, rs72552763 and rs34130495) in OCT1.Eighty‐six patients completed the trial. The mean difference (95% confidence interval) for dose adjusted morphine, M3G and M6G AUC was 0.9 (−0.7–2.4), −5.9 (−11.8 to −0.03) and −1.1 (−2.5–0.4) h/L*10−6, respectively, in patients with two reduced function alleles compared to patients with no reduced function alleles in OCT1. Accordingly, the (AUCM3G/Dose)/(AUCmorphine/Dose) and (AUCM6G/Dose)/(AUCmorphine/Dose) ratio was reduced, −1.8 (−3.2 to −0.4) and −0.4 (−0.7 to −0.03), respectively, when comparing the same groups. OCT1 variants had no influence on the experience of pain, adverse events or the number of PCA doses used. In conclusion, genetic variants in OCT1 had a small and clinically unimportant impact on the exposure of morphine after intravenous administration. Our results do not support pre‐emptive genotyping for OCT1 prior to morphine administration in patients scheduled for major surgery.

Quantifying the Pharmacodynamics of Morphine in the Treatment of Postoperative Pain in Preverbal Children.

While the pharmacokinetics of morphine in children have been studied extensively, little is known about the pharmacodynamics of morphine in this population. Here, we quantified the concentration‐effect relationship of morphine for postoperative pain in preverbal children between 0 and 3 years of age. For this, we applied item response theory modeling in the pharmacokinetic/pharmacodynamic analysis of COMFORT‐Behavior (COMFORT‐B) scale data from 2 previous clinical studies. In the model, we identified a sigmoid maximal efficacy model for the effect of morphine and found that in 26% of children, increasing morphine concentrations were not associated with lower pain scores (nonresponders to morphine up‐titration). In responders to morphine up‐titration, the COMFORT‐B score slowly decreases with increasing morphine concentrations at morphine concentrations >20 ng/mL. In nonresponding children, no decrease in COMFORT‐B score is expected. In general, lower baseline COMFORT‐B scores (2.1 points on average) in younger children (postnatal age <10.3 days) were found. Based on the model, we conclude that the percentage of children at a desirable COMFORT‐B score is maximized at a morphine concentration between 5 and 30 ng/mL for children aged <10 days, and between 5 and 40 ng/mL for children >10 days. These findings support a dosing regimen previously suggested by Krekels et al, which would put >95% of patients within this morphine target concentration range at steady state. Our modeling approach provides a promising platform for pharmacodynamic research of analgesics and sedatives in children.

Blood-Placental Barrier Transfers and Pharmacokinetics of Unbound Morphine in Pregnant Rats with Multiple Microdialysis Systems.

Microdialysis coupled to an analytical system can be used to continuously monitor unbound protein analytes in any biological fluid, tissue, or organ of animals. To date, no application of microdialysis has been performed to simultaneously monitor unbound morphine and its metabolites in the placenta and fetus of pregnant rats. Our hypothesis is that morphine and its metabolite penetrate the blood-placental barrier to reach the fetus during pregnancy. To investigate this hypothesis, this study aimed to develop a microdialysis experimental animal model coupled with an analytical system to monitor morphine and morphine-3-glucuronide (M3G) in the maternal blood, placenta, fetus, and amniotic fluid of pregnant rats. To determine the analytes in dialysates, a validated ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed. The pharmacokinetic results indicated that morphine fit well to a two-compartment model and exhibited nonlinear pharmacokinetic behavior within the dosage regimen. The M3G-to-morphine metabolite ratio, determined by the area under the concentration curve (AUC) ratio (AUCM3G/AUCmorphine), was approximately 5.40 in the maternal blood. In terms of tissue distribution, the mother-to-fetus transfer ratio (AUCfetus/AUCblood) of morphine and M3G was about 0.34 and 0.18, respectively. In conclusion, the high metabolite ratio suggests that morphine has the characteristics of rapid biotransformation, and the mother-to-fetus transfer ratio indicates that morphine and M3G partially transfer the blood-placental barrier in pregnant rats. This newly developed multiple microdialysis coupled to UHPLC-MS/MS system can be applied to the studies of maternal pharmacokinetics and blood-placental transfer in pregnant rats.

Sphingosine-1-phosphate Receptor Subtype 1 Antagonists may be the Unmet Medical Need for Morphine-induced Hyperalgesia and Antinociceptive Tolerance

Opioids such as morphine are frequently used for chronic pain management despite their many adverse effects. Ongoing research aims at either finding new treatments to replace opioids or reducing its heavy adverse effects due to long-term use: opioid-induced hyperalgesia and antinociceptive tolerance. In a recent study, Doyle et al. (2020) demonstrate that the activation of sphingosine-1-phosphate receptor subtype 1 (S1PR1) in the central nervous system contributes to morphine-induced hyperalgesia and antinociceptive tolerance in a rodent model of chronic pain. By targeting S1PR1 with molecules with functional antagonistic properties (some of which are FDA-approved for multiple sclerosis treatment), hyperalgesia and tolerance were significantly reduced without modifying morphine pharmacokinetics or efficacy.

Pharmacogenomics and Morphine.

Morphine is an opioid analgesic indicated in the treatment of acute and chronic moderate to severe pain. From a pharmacodynamic standpoint, morphine exerts its effects by agonizing mu‐opioid receptors predominantly, resulting in analgesia and sedation. Pharmacokinetically, morphine is primarily metabolized in the liver via glucuronidation by the enzyme uridine diphosphate glucuronosyltransferase family 2 member B7 and encounters the transporter proteins organic cation transporter isoform 1 and P‐glycoprotein (adenosine triphosphate–binding cassette subfamily B member 1) as it is being distributed throughout the body. The genes coding for the proteins impacting either the pharmacokinetics or pharmacodynamics of morphine may bear genetic variations, also known as polymorphisms, which may alter the function of the proteins in such a manner that an individual may have disparate treatment outcomes. The purpose of this review is to highlight some of the genes coding for proteins that impact morphine pharmacokinetics and pharmacodynamics and present some treatment considerations.

Postoperative breakthrough pain in paediatric cardiac surgery not reduced by increased morphine concentrations.

Morphine is commonly used for postoperative analgesia in children. Here we studied the pharmacodynamics of morphine in children after cardiac surgery receiving protocolized morphine. Data on morphine rescue requirements guided by validated pain scores in children (n = 35, 3-36 months) after cardiac surgery receiving morphine as loading dose (100 μg kg-1) with continuous infusion (40 μg kg-1 h-1) from a previous study on morphine pharmacokinetics were analysed using repeated time-to-event (RTTE) modelling. During the postoperative period (38 h (IQR 23-46)), 130 morphine rescue events (4 (IQR 1-5) per patient) mainly occurred in the first 24 h (107/130) at a median morphine concentration of 29.5 ng ml-1 (range 7-180 ng ml-1). In the RTTE model, the hazard of rescue morphine decreased over time (half-life 18 h; P < 0.001), while the hazard for rescue morphine (21.9% at 29.5 ng ml-1) increased at higher morphine concentrations (P < 0.001). In this study on protocolized morphine analgesia in children, rescue morphine was required at a wide range of morphine concentrations and further increase of the morphine concentration did not lead to a decrease in hazard. Future studies should focus on a multimodal approach using other opioids or other analgesics to treat breakthrough pain in children. In children receiving continuous morphine infusion, administration of rescue morphine is an indicator for insufficient effect or an event. Morphine rescue events were identified at a wide range of morphine concentrations upon a standardized pain protocol consisting of continuous morphine infusion and morphine as rescue boluses. The expected number of rescue morphine events was found to increase at higher morphine concentrations. Instead of exploring more aggressive morphine dosing, future research should focus on a multimodal approach to treat breakthrough pain in children.

Model-Informed Bayesian Estimation Improves the Prediction of Morphine Exposure in Neonates and Infants.

Pain control in infants is an important clinical concern, with potential long-term adverse neurodevelopmental effects. Intravenous morphine is routinely administered for postoperative pain management; however, its dose-concentration-response relationship in neonates and infants has not been well characterized. Although the current literature provides dosing guidelines for the average infant, it fails to control for the large unexplained variability in morphine clearance and response in individual patients. Bayesian estimation can be used to control for some of this variability. The authors aimed to evaluate morphine pharmacokinetics (PKs) and exposure in critically ill neonates and infants receiving standard-of-care morphine therapy and compare a population-based approach to the model-informed Bayesian techniques. The PKs and exposure of morphine and its active metabolites were evaluated in a prospective opportunistic PK study using 221 discarded blood samples from 57 critically ill neonates and infants in the neonatal intensive care unit. Thereafter, a population-based PK model was compared with a Bayesian adaptive control strategy to predict an individual's PK profile and morphine exposure over time. Among the critically ill neonates and infants, morphine clearance showed substantial variability with a 40-fold range (ie, 2.2 to 87.1, mean 23.7 L/h/70 kg). Compared with the observed morphine concentrations, the population-model based predictions had an R of 0.13, whereas the model-based Bayesian predictions had an R of 0.61. Model-informed Bayesian estimation is a better predictor of morphine exposure than PK models alone in critically ill neonates and infants. A large variability was also identified in morphine clearance. A further study is warranted to elucidate the predictive covariates and precision dosing strategies that use morphine concentration and pain scores as feedbacks.

Hyporesponsivity to mu-opioid receptor agonism in the Wistar-Kyoto rat model of altered nociceptive responding associated with negative affective state.

Chronic pain is often comorbid with anxiety and depression, altering the level of perceived pain, which negatively affects therapeutic outcomes. The role of the endogenous mu-opioid receptor (MOP) system in pain-negative affect interactions and the influence of genetic background thereon are poorly understood. The inbred Wistar-Kyoto (WKY) rat, which mimics aspects of anxiety and depression, displays increased sensitivity (hyperalgesia) to noxious stimuli, compared with Sprague-Dawley (SD) rats. Here, we report that WKY rats are hyporesponsive to the antinociceptive effects of systemically administered MOP agonist morphine in the hot plate and formalin tests, compared with SD counterparts. Equivalent plasma morphine levels in the 2 rat strains suggested that these differences in morphine sensitivity were unlikely to be due to strain-related differences in morphine pharmacokinetics. Although MOP expression in the ventrolateral periaqueductal gray (vlPAG) did not differ between WKY and SD rats, the vlPAG was identified as a key locus for the hyporesponsivity to MOP agonism in WKY rats in the formalin test. Moreover, morphine-induced effects on c-Fos (a marker of neuronal activity) in regions downstream of the vlPAG, namely, the rostral ventromedial medulla and lumbar spinal dorsal horn, were blunted in the WKY rats. Together, these findings suggest that a deficit in the MOP-induced recruitment of the descending inhibitory pain pathway may underlie hyperalgesia to noxious inflammatory pain in the WKY rat strain genetically predisposed to negative affect.

Exploring the Relationship Between Morphine Concentration and Oversedation in Children After Cardiac Surgery.

Titrating analgesic and sedative drugs in pediatric intensive care remains a challenge for caregivers due to the lack of pharmacodynamic knowledge in this population. The aim of the current study is to explore the concentration‐effect relationship for morphine‐associated oversedation after cardiac surgery in children aged 3 months to 3 years. Data on morphine dosing, as well as morphine plasma concentrations, were available from a previous study on the pharmacokinetics of morphine after cardiac surgery in children. Oversedation was defined as scores below 11 on the validated COMFORT–behavioral scale. Population pharmacokinetic‐pharmacodynamic modeling was performed in NONMEM 7.3. The probability of oversedation as a function of morphine concentration was best described using a step function in which the EC50 was 46.3 ng/mL. At morphine concentrations below the EC50, the probability of oversedation was 2.9% (0.4& to 18%), whereas above the EC50 percentages were 13% (1.9% to 52%) (median value [95% prediction interval from interindividual variability]). Additionally, the risk of oversedation was found to be increased during the first hours after surgery (P < .001) and was significantly lower during mechanical ventilation (P < .005). We conclude that morphine concentrations above approximately 45 ng/mL may increase the probability of oversedation in children after cardiac surgery. The clinician must evaluate, on a case‐by‐case basis, whether the analgesic benefits arising from dosing regimen associated with such concentrations outweigh the risks.

Activation of sphingosine-1-phosphate receptor subtype 1 in the central nervous system contributes to morphine-induced hyperalgesia and antinociceptive tolerance in rodents

Morphine-induced alterations in sphingolipid metabolism in the spinal cord and increased formation of the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) have been implicated in the development of morphine-induced hyperalgesia (OIH; increased pain sensitivity) and antinociceptive tolerance. These adverse effects hamper opioid use for treating chronic pain and contribute to dependence and abuse. S1P produces distinct effects through 5 G-protein-coupled receptors (S1PR1-5) and several intracellular targets. How S1P exerts its effects in response to morphine remains unknown. Here, we report that S1P contributes to the development of morphine-induced hyperalgesia and tolerance through S1P receptor subtype 1 (S1PR1) signaling in uninjured male and female rodents, which can be blocked by targeting S1PR1 with S1PR1 antagonists or RNA silencing. In mouse neuropathic pain models, S1PR1 antagonists blocked the development of tolerance to the antiallodynic effects of morphine without altering morphine pharmacokinetics and prevented prolonged morphine-induced neuropathic pain. Targeting S1PR1 reduced morphine-induced neuroinflammatory events in the dorsal horn of the spinal cord: increased glial marker expression, mitogen-activated protein kinase p38 and nuclear factor κB activation, and increased inflammatory cytokine expression, such as interleukin-1β, a cytokine central in the modulation of opioid-induced neural plasticity. Our results identify S1PR1 as a critical path for S1P signaling in response to sustained morphine and reveal downstream neuroinflammatory pathways impacted by S1PR1 activation. Our data support investigating S1PR1 antagonists as a clinical approach to mitigate opioid-induced adverse effects and repurposing the functional S1PR1 antagonist FTY720, which is FDA-approved for multiple sclerosis, as an opioid adjunct.