Recent Molecular Insights into Agonist-specific Binding to the Mu-Opioid Receptor

Opioid agonists produce their analgesic effects primarily by acting at the µ-opioid receptor (µOR). µOR agonists with different efficacies exert diverse molecular changes in the µOR which dictate the faith of the receptor’s signaling pathway and possibly it’s the degree of desensitization. Since the development of the active conformations of the µOR, growing data have been published in relation to ligand-specific changes in µOR activation. In this regard, this review summarizes recent data regarding the most studied opioid agonists in in silico µOR activation, including how these ligands are recognized by the µOR, how their binding signal is transmitted toward the intracellular parts of the µOR, and finally, what type of large-scale movements do these changes trigger in the µOR’s domains

Perifériás és centrális receptorok részvétele opioidok fájdalomcsillapító hatásában és mellékhatás spektrumában.Korai drog expozició (perinatális és adoleszcensz) hatásának vizsgálata patkányon = On the role of central and peripheral receptors in the antinociceptive action and side effects of opioids.The influence of early (perinatal and in adolescent age) drug exposition on antinociception

A fájdalom terápiájának megoldása sürgető és releváns igény. Korábban publikáltunk néhány az agyba limitáltan penetráló morfinant. Jelen munkában kb. 30 új származékot vizsgáltunk. Perifériás vs centrális analgetikus aktivitásuk 40-400, a rosszul penetráló opioid antagonisták gátolják hatásukat, intrinsic efficacy-juk magas (perifériás hatékonyság markere az általunk kidolgozott módszer szerint ), gátló hatásuk patkány DRG sejteken perifériás támadáspont mellett szól. Morfintoleráns egérben spinálisan adva a DPDPE gátolja, míg TIPPszi potencírozza a DAMGO antinociceptív hatását. Patkányon mind naiv mind toleráns állatban a hatás potencirozó. A prodynorfin génexpresszió és dinorfin szint a dependenciáért felelős agyi régiókban módosul perifériás opioidok hatására. A perinatalisan drog expozíciónak kitett patkány anyák korai adoleszcens korú utódainak testsúlya, adaptációs képessége szignifikánsan csökkent, erőltetett úszás teszten depressziót jeleztek, fizikálisan dependensekké, vulnerábilissá váltak. Az anyai viselkedés romlott. Konklúzió: új morfinánok segítségével a C-6 szubsztitució prominens szerepét demonstráltuk a perifériás hatékonyság erősödésében, a preemptiv analgéziában, limitált légzésdepresszió és pszichológiai dependencia mellett. Az eredmény elméleti jelentősége mellett gyakorlati fontosságú a klinikum számára. Kimutattuk továbbá, hogy perinatálisan stimuláns ill. opioid kábítószerekkel kezelt patkányok utódai vulnerábilissá válnak, az abúzus veszélye nő. | There is a permanent and relevant need to manage pain. Previously we published opioids with limited access to the brain. 30 new derivatives were studied in rodents and found to be more potent analgesics, than morphine (Mo). Their peripheral vs central activites were between 40-400, the analgesic action was inhibited by poorly penetrating antagonists contrast to Mo, they block DRG cells, their intrinsic efficacy (a good marker of peripheral activity), is much higher than Mo assessed by a method elaborated by us, suggesting a peripheral site of action. DPDP administered spinally to Mo tolerant mice inhibited, while TIPPsi potentiated DAMGO analgesia.. We observed potentiation both in naive and tolerant rat. Prodynorphin gene expression and dynorphin level in brain regions responsible for the development of dependence were modified by opioids. The body weight, the adaptive behaviour of early adolescent offspring of perinatally Mo and ecstasy exposed dams decreased, they show depression in swimming test, they became physically dependent, and vulnerable to addiction. The maternal behavior of dams was disturbed. Conclusion: new data on the mechanisms of preemptive analgesia were obtained by new C-6 substituted morphinans. Respiratory depression and psychological dependence were limited. This finding beside its basic importance has practical importance too.Furthermore the offspring of dams perinatally exposed to substances of drug abuse became vulnerable and prone to be addict.

Shedding light on the pharmacological interactions between µ-opioid analgesics and angiotensin receptor modulators:A new option for treating chronic pain

The current protocols for neuropathic pain management include µ-opioid receptor (MOR) analgesics alongside other drugs; however, there is debate on the effectiveness of opioids. Nevertheless, dose escalation is required to maintain their analgesia, which, in turn, contributes to a further increase in opioid side effects. Finding novel approaches to effectively control chronic pain, particularly neuropathic pain, is a great challenge clinically. Literature data related to pain transmission reveal that angiotensin and its receptors (the AT1R, AT2R, and MAS receptors) could affect the nociception both in the periphery and CNS. The MOR and angiotensin receptors or drugs interacting with these receptors have been independently investigated in relation to analgesia. However, the interaction between the MOR and angiotensin receptors has not been excessively studied in chronic pain, particularly neuropathy. This review aims to shed light on existing literature information in relation to the analgesic action of AT1R and AT2R or MASR ligands in neuropathic pain conditions. Finally, based on literature data, we can hypothesize that combining MOR agonists with AT1R or AT2R antagonists might improve analgesia

Similarity and dissimilarity in antinociceptive effects of dipeptidyl-peptidase 4 inhibitors, Diprotin A and vildagliptin in rat inflammatory pain models following spinal administration.

Dipeptidyl-peptidase 4 (DPP4) enzyme is involved in the degradation of many biologically active peptides including opioids. Its role in pain transmission is poorly elucidated. Recently we reported on the spinal antihyperalgesic effects of DPP4 inhibitors, Ile-Pro-Ile (Diprotin A) and vildagliptin in carrageenan-evoked acute inflammatory pain in rats. The present study investigated the effects of intrathecal (it.) diprotin A and vildagliptin in Complete Freund's Adjuvant- (CFA) and formalin induced pain in rats. The former assay can model the subchronic inflammatory pain condition and the later one reflects both acute tonic and inflammatory pain conditions. The involvement of opioid receptor (OR) subtypes, Y1-, and GLP1 receptors were also investigated. In CFA pain model it. diprotin A or vildagliptin dose-dependently inhibits hyperalgesia in ipsilateral while has no effect in contralateral paws. The peak effect was achieved 30 min following drug administration which was used for further analysis. Both compounds showed naltrexone reversible antihyperalgesia. Co-administration of OR-subtype-selective antagonists with diprotin A and vildagliptin revealed involvement of μ and δ > μ opioid receptors, respectively. Co-administered Y1 but not GLP1 receptor antagonists reversed the antihyperalgesic action of both DPP4 inhibitors. In touch-hypersensitivity both compounds were ineffective. In formalin test only diprotin A showed μ and δ OR-mediated antinociception and only in the 2nd phase. This effect was Y1 or GLP-1 receptor antagonist insensitive. In conclusion, diprotin A and vildagliptin display antinociception of different mechanisms of action in subchronic inflammatory pain. Furthermore, the spinal pain relay points of inflammatory pain of acute or subchronic conditions were more effectively affected by diprotin A than vildagliptin which needs future elucidation

Efficacy-based perspective to overcome reduced opioid analgesia of advanced painful diabetic neuropathy in rats

Reduction of the opioid analgesia in diabetic neuropathic pain (DNP) results from mu-opioid receptor (MOR) reserve reduction. Herein, we examined the antinociceptive and antiallodynic actions of a novel opioid agonist 14-O-methymorphine-6-O-sulfate (14-O-MeM6SU), fentanyl and morphine in rats with streptozocin-evoked DNP of 9-12 weeks following their systemic administration. The antinociceptive dose-response curve of morphine but not of 14-O-MeM6SU or fentanyl showed a significant right-shift in diabetic compared to non-diabetic rats. Only 14-O-MeM6SU produced antiallodynic effects in doses matching antinociceptive doses obtained in non-diabetic rats. Co-administered naloxone methiodide (NAL-M), a peripherally acting opioid receptor antagonist failed to alter the antiallodynic effect of test compounds, indicating the contribution of central opioid receptors. Reduction in spinal MOR binding sites and loss in MOR immunoreactivity of nerve terminals in the spinal cord and dorsal root ganglia in diabetic rats were observed. G-protein coupling assay revealed low efficacy character for morphine and high efficacy character for 14-O-MeM6SU or fentanyl at spinal or supraspinal levels (E-max values). Furthermore, at the spinal level only 14-O-MeM6SU showed equal efficacy in G-protein activation in tissues of diabetic- and non-diabetic animals. Altogether, the reduction of spinal opioid receptors concomitant with reduced analgesic effect of morphine may be circumvented by using high efficacy opioids, which provide superior analgesia over morphine. In conclusion, the reduction in the analgesic action of opioids in DNP might be a consequence of MOR reduction, particularly in the spinal cord. Therefore, developing opioids of high efficacy might provide analgesia exceeding that of currently available opioids

On the role of peripheral sensory and gut mu opioid receptors: Peripheral analgesia and tolerance

There is growing evidence on the role of peripheral \ub5-opioid receptors (MORs) in analgesia and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate to severe pain, and their efficacy in the alleviation of pain is well recognized. Unfortunately, chronic treatment with opioid analgesics induces central analgesic tolerance, thus limiting their clinical usefulness. Numerous molecular mechanisms, including receptor desensitization, G-protein decoupling, \u3b2-arrestin recruitment, and alterations in the expression of peripheral MORs and microbiota have been postulated to contribute to the development of opioid analgesic tolerance. However, these studies are largely focused on central opioid analgesia and tolerance. Accumulated literature supports that peripheral MORs mediate analgesia, but controversial results on the development of peripheral opioid receptors-mediated analgesic tolerance are reported. In this review, we offer evidence on the consequence of the activation of peripheral MORs in analgesia and analgesic tolerance, as well as approaches that enhance analgesic efficacy and decrease the development of tolerance to opioids at the peripheral sites. We have also addressed the advantages and drawbacks of the activation of peripheral MORs on the sensory neurons and gut (leading to dysbiosis) on the development of central and peripheral analgesic tolerance

Glycine transporter inhibitors

Interneurons operating with glycine neurotransmitter are involved in the regulation of pain transmission in the dorsal horn of the spinal cord. In addition to interneurons, glycine release also occurs from glial cells neighboring glutamatergic synapses in the spinal cord. Neuronal and glial release of glycine is controlled by glycine transporters (GlyTs). Inhibitors of the two isoforms of GlyTs, the astrocytic type-1 (GlyT-1) and the neuronal type-2 (GlyT-2), decrease pain sensation evoked by injuries of peripheral sensory neurons or inflammation. The function of dorsal horn glycinergic interneurons has been suggested to be reduced in neuropathic pain, which can be reversed by GlyT-2 inhibitors (Org-25543, ALX1393). Several lines of evidence also support that peripheral nerve damage or inflammation may shift glutamatergic neurochemical transmission from N-methyl-D aspartate (NMDA) NR1/NR2A receptor- to NR1/NR2B receptor-mediated events (subunit switch). This pathological overactivation of NR1/NR2B receptors can be reduced by GlyT-1 inhibitors (NFPS, Org-25935), which decrease excessive glycine release from astroglial cells or by selective antagonists of NR2B subunits (ifenprodil, Ro 25-6981). Although several experiments suggest that GlyT inhibitors may represent a novel strategy in the control of neuropathic pain, proving this concept in human beings is hampered by lack of clinically applicable GlyT inhibitors. We also suggest that drugs inhibiting both GlyT-1 and GlyT-2 non-selectively and reversibly, may favorably target neuropathic pain. In this paper we overview inhibitors of the two isoforms of GlyTs as well as the effects of these drugs in experimental models of neuropathic pain. In addition, the possible mechanisms of action of the GlyT inhibitors, i.e. how they affect the neurochemical and pain transmission in the spinal cord, are also discussed. The growing evidence for the possible therapeutic intervention of neuropathic pain by GlyT inhibitors further urges development of drugable compounds, which may beneficially restore impaired pain transmission in various neuropathic conditions