RESUMEN
Some insects produce venoms to defend against predators and directly interact with opioid receptors. In the present study, it was identified two alkaloids in the wasp venom species Hymenoepimecis bicolor. It was demonstrated that these could act as potential inhibitors of opioid receptors through their robust affinity to the receptors. The interaction profile was given to opioid receptors (µOR), with 60% of targets similar to alkaloid 1, with 0.25 probability, and 46.7% of targets similar to alkaloid 2, with a probability 0.17 of affinity as a target, which is considered signaling macromolecules and can mediate the most potent analgesic and addictive properties of opiate alkaloids. Notably, both alkaloids showed -7.6 kcal/mol affinity to the morphine agonies through six residues, Gly124, Asp147, Trp293, Ile296, Ile322, and Tyr326. These observations suggest further research on opioid receptors using in vitro studies of possible therapeutic applications.Communicated by Ramaswamy H. Sarma.
Asunto(s)
Alcaloides , Venenos , Receptores Opioides , Morfina/química , Morfina/farmacología , Alcaloides/farmacologíaRESUMEN
Abstract: Morphine is a well-characterized and effective analgesic commonly used to provide pain relief to patients suffering from both acute and chronic pain conditions. Despite its widespread use and effectiveness, one of the major drawbacks of morphine is its relatively short half-life of approximately 4 h. This short half-life often necessitates multiple administrations of the drug each day, which may contribute to both dependence and tolerance to morphine. Here, we tested the analgesic properties of a new polymer form of morphine known as PolyMorphine. This polymer has monomeric units of morphine incorporated into a poly(anhydride-ester) backbone that has been shown to hydrolyze into free morphine in vitro. Using an animal model of chronic pain, the spared nerve injury surgery, we showed that PolyMorphine is able to block spared nerve injury-induced hypersensitivity in mice for up to 24-h post-administration. Free morphine was shown to only block spared nerve injury-induced hypersensitivity for up to 2-h post-injection. PolyMorphine was also shown to act through the mu opioid receptor due to the ability of naloxone (a mu opioid receptor antagonist) to block PolyMorphine-induced analgesia in spared nerve injury animals pretreated with PolyMorphine. Additionally, we observed that PolyMorphine causes similar locomotor and constipation side effects as free morphine. Finally, we investigated if PolyMorphine had any effects in a non-evoked pain assay, conditioned place preference. Pretreatment of spared nerve injury mice with PolyMorphine blocked the development of conditioned place preference for 2-methyl-6-(phenylethynyl)pyridine (MPEP), a short-lasting mGluR5 antagonist with analgesic-like properties. Free morphine does not block the development of preference for MPEP, suggesting that PolyMorphine has longer lasting analgesic effects compared to free morphine. Together, these data show that PolyMorphine has the potential to provide analgesia for significantly longer than free morphine while likely working through the same receptor.
Asunto(s)
Analgésicos Opioides/farmacología , Morfina/farmacología , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Receptores Opioides mu/efectos de los fármacos , Animales , Tolerancia a Medicamentos/fisiología , Ratones Endogámicos C57BL , Morfina/química , Naloxona/farmacología , Antagonistas de Narcóticos/farmacologíaRESUMEN
The detailed knowledge of the solid forms of a drug is a key element in pharmaceutical development. Morphine (MOR) is an opiate alkaloid widely used to treat severe acute and chronic pain. Much of the available information on its solid state dates from several decades ago. In order to obtain updated and reliable information, 1-dimensional (1D) and 2-dimensional solid-state nuclear magnetic resonance spectroscopy were used and complemented with powder X-ray diffraction, FTIR, and Raman spectroscopy and thermal analysis. 13C cross-polarization with magic angle spinning 1D spectra accomplish a complete identification of the related forms of MOR. Remarkably, 1H-13C heteronuclear correlation spectra together with FTIR results gave clear evidence that neither MOR nor its hydrate crystallizes as a zwitterion. Our results indicate that the hydrogen bonds in the anhydrate forms have a different nature or strength than in their respective hydrates. The unique information obtained would be useful for the characterization of MOR as a bulk drug, dosage forms, and future developments.
Asunto(s)
Morfina/química , Rastreo Diferencial de Calorimetría/métodos , Química Farmacéutica/métodos , Cristalización/métodos , Cristalografía por Rayos X/métodos , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética/métodos , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Espectrometría Raman/métodos , Agua/química , Difracción de Rayos X/métodosRESUMEN
Gas chromatography/combustion/mass spectrometry (GC-C-MS) and elemental analysis/mass spectrometry (EA-MS) techniques are proposed to estimate delta(13)C and delta(15)N values in heroin, morphine, cocaine and hemp leaves, for the purposes of tracing the geographical origins of seized drugs. The values of isotope ratios for pure drugs and drugs with impurities were compared. It was demonstrated that large samples (up to 3 x 10(-6) g C) were combusted completely, so that the results obtained were valid. The data are considered to be an essential supplement to a wide-scale database designed specifically for the delta(13)C and delta(15)N values of drugs. The potential forensic and academic significance of the results is discussed.
Asunto(s)
Drogas Ilícitas/análisis , Drogas Ilícitas/química , Afganistán , Cannabis/química , Isótopos de Carbono , Cocaína/análisis , Cocaína/química , Colombia , Contaminación de Medicamentos , Cromatografía de Gases y Espectrometría de Masas , Heroína/análisis , Heroína/química , Corea (Geográfico) , Morfina/análisis , Morfina/química , Isótopos de Nitrógeno , Federación de Rusia , UcraniaRESUMEN
Este tabajo presenta un descripción breve de las evidencias que señalan el papel de los péptidos opioides en el control del dolor. Se describe el papel inhibidor de la ß-endorfina y de la Met-encefalina en los tejidos periféricos y, se sugiere una acción local en el sitio de la inflamación. Asimismo, se hace referencia a los sistemas endógenos de inhibición del dolor tanto a los segmentarios inherentes a la organización celular de la médula espinal, como a los sistemas descendentes, que tienen su origen en diversos núcleos del tallo cerebral. Las conexiones eferentes de estos sistemas siguen el trayecto del fascículo dorsolateral para terminar en las astas dorsales de la médula espinal, en donde ejercen su acción. Con esta idea, se analiza la participación de la ß-endorfina y los péptidos derivados en la analgesia. También se discute el papel que desempeñan los receptores µ, delta y kappa en el control del dolor y los ligandos endógenos que se unen a estos receptores. Las evidencias sugieren que la analgesia opioide, es el resultado predominante de la activación de los receptores µ, aunque los delta y los kappa pueden potenciar este efecto. Con respecto a los receptores delta y sus ligandos con mayor afinidad, las encefalinas tienen una participación indirecta en la analgesia. En relación a los receptores kappa y sus ligando más afines, las dinorfinas, los datos publicados son controvertidos. Por último, se hace referencia a los efectos paradójicos de la naloxona en el control del dolor, pues a dosis altas, aumentan las respuestas algésicas (hiperalgesia) y las dosis muy bajas producen analgesia