New insights into enhancing morphine analgesia : from glia to pharmacokinetics

Opioid analgesics are effective in relieving acute and chronic pain. However, adverse effects and the development of opioid dependence and tolerance may restrict the use of opioids and result in inadequate pain relief. The effects of four structurally and functionally different drugs already on the market, ibudilast, atipamezole, spironolactone, and ketamine, were studied in coadministration with morphine, the prototypical mu-opioid receptor agonist. Experiments were conducted using thermal and mechanical tests of nociception in male Sprague-Dawley rats. Morphine tolerance was produced during four days by subcutaneous or intrathecal delivery of morphine. Drug and metabolite concentrations were measured using high-pressure liquid chromatography-tandem mass spectrometry. The objective of the thesis study was to search for potential drugs to augment morphine antinociception and prevent opioid tolerance. Ibudilast, a phosphodiesterase and macrophage inhibitory factor inhibitor, had transient sedative effects, but it restored the antinociceptive effect of morphine in morphine-tolerant rats after single and repeated administration. It did not prevent the development of opioid tolerance. Atipamezole, an alpha-2-adrenoceptor antagonist used for the reversal of sedation in animals during anesthesia, was effective in augmenting intrathecal morphine antinociception in both opioid-naïve and opioid-tolerant animals. These effects were observed at doses lower than those required for the antagonism of alpha-2-adrenoceptors. In subcutaneous administration, low doses of atipamezole did not influence morphine antinociception. The mineralocorticoid receptor antagonist spironolactone dose-dependently enhanced morphine antinociception. This effect was mediated via the increased access of morphine to the central nervous system by the inhibition of the efflux protein P-glycoprotein. Spironolactone did not inhibit the metabolism of morphine to the pronociceptive metabolite morphine-3-glucuronide, and it did not prevent the development of opioid tolerance. The effects of ketamine in augmenting opioid analgesia in tolerance are thought to result from a beneficial pharmacodynamic interaction. When acute ketamine was administered to rats under chronic morphine treatment, the brain concentrations of morphine, ketamine and norketamine were increased compared with the situation where either morphine treatment or acute ketamine were administered alone. The results indicate a potentially beneficial pharmacokinetic interaction between the two drugs. The results of the thesis study demonstrate that ibudilast and atipamezole modulate nociception at systemic and spinal levels in preclinical models of pain, and they may prove advantageous as an adjuvant to opioid therapy. Spironolactone had a pharmacokinetic interaction with morphine, leading to increased morphine concentrations in the central nervous system. Ketamine, a drug used for the treatment of opioid tolerance in cancer patients, may undergo previously unrecognized beneficial pharmacokinetic interactions with morphine.Opioidit, morfiinin kaltaiset kipulääkkeet, ovat tehokkaimpia lääkkeitä etenkin akuutin kivun hoidossa. Haittavaikutukset ja opioideille muodostuva toleranssi eli sietokyvyn lisääntyminen saattavat kuitenkin rajoittaa opioidien käyttöä ja johtaa epätyydyttävään kivun lievitykseen pitkittyneessä kivussa. Tässä tutkimuksessa tarkasteltiin neljää sekä rakenteellisesti että toiminnallisesti erilaista lääkettä, ibudilastia, atipametsolia, spironolaktonia ja ketamiinia, kokeellisissa opioidihoidon rottamalleissa. Tutkimuksessa käytettiin ihmisillä käytettävien kiputestien kaltaisia kuuman ja mekaanisen kivun väistötestejä sekä sedaatiota ja koordinaatiota mittaavia testejä. Opioidihoidon eri vaiheita mallinnettiin aina akuutista kerta-annosta nelipäiväiseen opioditoleranssimalliin. Opioideja ja tutkimuslääkkeitä annettiin joko nahanalaisesti tai suoraan aivo-selkäydinnesteeseen tutkimusmallista ja -lääkkeestä riippuen. Lääkkeiden ja niiden hajoamistuotteiden pitoisuuksia mitattiin kromatografialla. Tutkimuksen tarkoituksena oli etsiä uusia lääkehoitomahdollisuuksia opioidihoidon tehostamiseksi ja etenkin opioidien vasteen palauttamiseksi. Astmalääke ibudilastia on tutkittu usean neurologisen sairauden hoitoon mahdollisen keskushermoston gliasolujen patologisen aktivaation estäjänä. Sillä oli rottamallissa lievä sedatiivinen vaikutus, mutta se palautti tehokkaasti morfiinin kipua lievittävän vasteen opioiditoleranssissa. Se ei kuitenkaan estänyt opioiditoleranssin kehittymistä. Ibudilastin vaikutusmekanismi vaatii lisäselvityksiä. Alfa-2-reseptoreiden estäjä atipametsolia käytetään eläinlääkkeenä anestesian jälkeisessä eläinten herätyksessä. Aivo-selkäydinnesteeseen annettuna atipametsoli lisäsi morfiinin antinosiseptiivista vastetta sekä akuutissa yhteisannossa morfiinin kanssa sekä opioiditoleranssimallissa. Nämä vaikutukset havaittiin hyvin pienillä annoksilla atipametsolia. Nahan alle annosteltuna vastaavaa yhteisvaikutusta morfiinin kanssa ei havaittu. Nesteenpoistolääkkeenä käytetty spironolaktoni lisäsi morfiinin antinosiseptiivista vaikutusta sekä akuutissa yhteisannossa että toleranssimallissa. Pitoisuustutkimuksissa havaittiin spironolaktonin lisäävän morfiinin keskushermostopitoisuuksia. Tämä vaikutus välittyi todennäköisesti lääkeainekuljetusproteiini P-glykoproteiinin estovaikutuksen kautta. Spironolaktoni ei ehkäissyt opioiditoleranssin kehitystä. NMDA-reseptorin estäjä ketamiinin on ajateltu palauttavan opioidien vastetta reseptorien kautta välittyvien farmakodynaamisten yhteisvaikutusten kautta. Lääkkeiden pitoisuusmittauksissa havaittiin, että morfiinitoleranteilla rotilla morfiinin, ketamiinin ja norketamiinin keskushermostopitoisuudet olivat yhteisannossa lisääntyneet huomattavasti verrattuna tilanteeseen, jossa lääkkeitä annettiin yksinään. Ketamiinin hyödyllinen vaikutus opioiditoleranssissa saattaa siis osittain perustua myös farmakokineettiseen yhteisvaikutukseen

Uusien kipulääkkeiden kehitys on haastavaa

Uudella mekanismilla vaikuttavien kipulääkkeiden kehitys on haastavaa. Käymme läpi joitakin onnistuneita ja pitkälle edenneitä kehitysprojekteja sekä hieman historiaa

Glymfaattinen järjestelmä avaa aivojen padot

Peer reviewe

Selective detection of morphine in the presence of paracetamol with anodically pretreated dual layer Ti/tetrahedral amorphous carbon electrodes

We investigated the effect of anodic treatment of titanium/tetrahedral amorphous carbon electrodes on the electrochemical detection of morphine and paracetamol. The anodic treatment caused both oxidation of the carbon and, more importantly, exposure and oxidation of the underlying Ti layer. This treatment anodically shifted the oxidation potential of paracetamol while that of morphine remained unaffected. The resulting electrode also showed better selectivity than a ta-C electrode without Ti. After anodic treatment at 2.5 V, selective detection of morphine with a physiologically meaningful detection limit of 9.8 nM and a linear range of 0.1-10 mu M was obtained in the presence of 100 mu M paracetamol.Peer reviewe

Simultaneous electrochemical detection of tramadol and O-desmethyltramadol with Nafion-coated tetrahedral amorphous carbon electrode

Tramadol (TR) is a member of the opioid family and is widely used for pain treatment in clinical patient care. The analgesic effect of tramadol is induced primarily by its main metabolite Odesmethyltramadol (ODMT). Due to interindividual differences in the TR metabolism to ODMT, the responses to TR vary highly between patients. Thus, a fast and selective method for simultaneous detection of TR and ODMT would increase the patient safety and pain treatment efficacy. In this study, a tetrahedral amorphous carbon (ta-C) electrode coated with a thin dip-coated recast Nafion membrane was fabricated for selective electrochemical determination of TR and ODMT. With this Nafion/ta-C electrode, simultaneous detection of TR and ODMT was achieved with linear ranges of 1-12.5 mu M and 1-15 mu M, respectively. The limits of detection were 131 nM for TR and 209 nM for ODMT. Both analytes were also measured in the presence of several common interferents, demonstrating the high selectivity of the fabricated electrode. In addition, the effect of pH on the peak potential was studied to observe the electrochemical behavior of the analytes at the electrode. Finally, clinically relevant concentrations of TR and ODMT were simultaneously detected from diluted human plasma to assess the applicability of the electrode in real samples. The fabricated Nafion/ta-C electrode was found successful in the simultaneous electrochemical detection of TR and ODMT in both buffer solution and in human plasma. (C) 2018 Elsevier Ltd. All rights reserved.Peer reviewe

Neurophysiological response properties of medullary pain-control neurons following chronic treatment with morphine or oxycodone : modulation by acute ketamine

Descending facilitatory circuitry that involves the rostroventromedial medulla (RVM) exerts a significant role in the development of antinociceptive tolerance and hyperalgesia following chronic morphine treatment. The role of the RVM in the development of antinociceptive tolerance to oxycodone, another clinically used strong opioid. is not yet known. Ketamine, an N-methyl-o-aspartate (NMDA) receptor antagonist, attenuates opioid antinociceptive tolerance, but its effect on RVM cell discharge in opioid-tolerant animals is not known. Here, we compared chronic effects of morphine and oxycodone on the discharge properties of RVM cells and attempted to attenuate chronic treatment-induced changes with ketamine. Parallel recordings of RVM cell discharge and limb withdrawal response were performed under light pentobarbital anesthesia in male rats following sustained systemic treatment with morphine or oxycodone at equianalgesic doses. Ongoing activity and the response to noxious heat and pinch were determined in pronociceptive RVM ON-cells and antinociceptive OFF-cells on the sixth treatment day. Proportions of RVM cell types were not changed. Chronic oxycodone induced antinociceptive tolerance both in limb withdrawal and RVM cell activity. Chronic morphine induced antinociceptive tolerance in limb withdrawal that was accompanied by pronociceptive heat response changes in RVM ON- and OFF-cells. A behaviorally subantinociceptive dose of acute ketamine reversed antinociceptive tolerance both to morphine and oxycodone in limb withdrawal and reversed the chronic morphine-induced pronociceptive discharge changes in RVM cells. The results indicate that an NMDA receptor-dependent descending pronociceptive circuitry involving the RVM has an important role in behavioral antinociceptive tolerance to morphine but not oxycodone. NEW & NOTEWORTHY Morphine and oxycodone are two clinically used strong opioids. Chronic treatment with oxycodone as well as morphine can lead to analgesic tolerance and paradoxical hyperalgesia. Here we show that an N-methyl-n-aspartate receptor-dependent pronociceptive change in discharge properties of rostroventromedial medullary neurons controlling spinal nociception has an important role in antinociceptive tolerance to morphine but not oxycodone. Interestingly, chronic oxycodone did not induce pronociceptive changes in the rostroventromedial medulla.Peer reviewe

Rifampin Reduces the Plasma Concentrations of Oral and Intravenous Hydromorphone in Healthy Volunteers

Peer reviewe

Vanhuksen hermovauriokipua on hoidettava tehokkaasti

Kommentt

Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia

The glymphatic system is responsible for brain-wide delivery of nutrients and clearance of waste via influx of cerebrospinal fluid (CSF) alongside perivascular spaces and through the brain. Glymphatic system activity increases during sleep or ketamine/xylazine (K/X) anesthesia, yet the mechanism(s) facilitating CSF influx are poorly understood. Here, we correlated influx of a CSF tracer into the brain with electroencephalogram (EEG) power, heart rate, blood pressure, and respiratory rate in wild-type mice under six different anesthesia regimens. We found that glymphatic CSF tracer influx was highest under K/X followed by isoflurane (ISO) supplemented with dexmedetomidine and pentobarbital. Mice anesthetized with a-chloralose, Avertin, or ISO exhibited low CSF tracer influx. This is the first study to show that glymphatic influx correlates positively with cortical delta power in EEG recordings and negatively with beta power and heart rate.Peer reviewe

Could dexmedetomidine be repurposed as a glymphatic enhancer?

Cerebrospinal fluid (CSF) flows through the central nervous system (CNS) via the glymphatic pathway to clear the interstitium of metabolic waste. In preclinical studies, glymphatic fluid flow rate increases with low central noradrenergic tone and slow-wave activity during natural sleep and general anesthesia. By contrast, sleep deprivation reduces glymphatic clearance and leads to intracerebral accumulation of metabolic waste, suggesting an underlying mechanism linking sleep disturbances with neurodegenerative diseases. The selective alpha(2)-adrenergic agonist dexmedetomidine is a sedative drug that induces slow waves in the electroencephalogram, suppresses central noradrenergic tone, and preserves glymphatic outflow. As recently developed dexmedetomidine formulations enable self-administration, we suggest that dexmedetomidine could serve as a sedative-hypnotic drug to enhance clearance of harmful waste from the brain of those vulnerable to neurodegeneration