Pharmacogenetics of analgesic drugs

• Individual variability in pain perception and differences in the efficacy of analgesic drugs are complex phenomena and are partly genetically predetermined. • Analgesics act in various ways on the peripheral and central pain pathways and are regarded as one of the most valuable but equally dangerous groups of medications. • While pharmacokinetic properties of drugs, metabolism in particular, have been scrutinised by genotype–phenotype correlation studies, the clinical significance of inherited variants in genes governing pharmacodynamics of analgesics remains largely unexplored (apart from the µ-opioid receptor). • Lack of replication of the findings from one study to another makes meaningful personalised analgesic regime still a distant future. • This narrative review will focus on findings related to pharmacogenetics of commonly used analgesic medications and highlight authors’ views on future clinical implications of pharmacogenetics in the context of pharmacological treatment of chronic pain

The Local Anesthetic and Pain Relief Activity of Alkaloids

Alkaloids have been known for several centuries and have been mainly obtained from natural sources that presented important properties with biochemical, pharmacological, and medical effects in living organisms. Alkaloids are derived from amino acids like other important molecules in the functioning of life in our body. Hence, alkaloids are considered as pharmacologically important. Alkaloids are secondary metabolites widely distributed in leaves, stem, root, and fruits of plants which synthesize them. However, administration and consumption of them at right doses are beneficial in terms of health; excess doses will be definitely poisonous and may cause even death. The pharmacological activities of alkaloids are quite diverse. They are important natural products with a wide range of medicinal properties including relief of pain (e.g., morphine), analgesic (e.g., codeine), antiarrhythmic (e.g., quinidine), antibacterial (e.g., chelerythrine), antiasthma (e.g., ephedrine), cholinomimetic (e.g., galantamine), and vasodilatory (e.g., vincamine)

Ocular sequelae from the illicit use of class A drugs

Aim: To highlight the changes that may take place in the visual system of the class A drug abuser. Methods: A literature review was carried out of ocular/visual sequelae of the more common class A drugs. These include stimulants (cocaine and crack cocaine), narcotics (heroin, morphine, methadone) and hallucinogenics (ecstasy, lysergic acid diethylamide, magic mushrooms, mescaline, phencyclidine). Results: Ocular sequelae affecting visual acuity, the eye and its adnexa, ocular posture and ocular motility can result from recreational use of these drug(s). Conclusions: Awareness of the consequences of illicit drug use should lead to more pertinent questioning during history-taking

Nanobiosensors for detection of opioids: A review of latest advancements

Opioids are generally used as analgesics in pain treatment. Like many drugs, they have side effects when overdosed and can cause addiction problems. Illegal drug use and misuse are becoming a major concern for authorities worldwide; thus, it is critical to have precise procedures for detecting them in confiscated samples, biological fluids, and wastewaters. Routine blood and urine tests are insufficient for highly selective determinations and can cause cross-reactivities. For this purpose, nanomaterial-based biosensors are great tools to determine opioid intakes, continuously monitoring the drugs with high sensitivity and selectivity even at very low sample volumes. Nanobiosensors generally comprise a signal transducer nanostructure in which a biological recognition molecule is immobilized onto its surface. Lately, nanobiosensors have been extensively utilized for the molecular detection of opioids. The usage of novel nanomaterials in biosensing has impressed researchers who work on developing biosensors. Nanomaterials with a large surface area have been used to develop nanobiosensors with shorter reaction times and higher sensitivity than conventional biosensors. Colorimetric and fluorescence sensing methods are two kinds of optical sensor systems based on nanomaterials. Noble metal nanoparticles (NPs), such as silver and gold, are the most frequently applied nanomaterials in colorimetric techniques, owing to their unique optical feature of surface plasmon resonance. Despite the progress of an extensive spectrum of nanobiosensors over the last two decades, the future purpose of low-cost, high-throughput, multiplexed clinical diagnostic Lab-on-a-Chip instruments has yet to be fulfilled. In this review, a concise overview of opioids (such as tramadol and buprenorphine, oxycodone and fentanyl, methadone and morphine) is provided as well as information on their classification, mechanism of action, routine tests, and new opioid sensing technologies based on various NPs. In order to highlight the trend of nanostructure development in biosensor applications for opioids, recent literature examples with the nanomaterial type, target molecules, and their limits of detection are discussed

From the Origins of the Opioid Use (and Misuse) to the Challenge of Opioid-Free Pain Management in Surgery

Pain is a physiologic mechanism of the human body. Early cultures believed pain to have demonic and spiritual origins. In the early nineteenth century, morphine was first isolated by the German pharmacist Friedrich Wilhelm Adam Ferdinand Serturner. Since then, synthetic opioids and other derivatives of morphine have been developed for a wide variety of purposes, including pain relief during surgery. Opioids mainly act through the stimulation of μ-receptors, which has inhibitory effects on the propagation of pain signals to the brain. However, opioids also have unwanted side effects like nausea, vomiting, constipation, postoperative sedation, dizziness, and addiction, and are associated with significant morbidity, prolong hospital stays, increase use of medications needed to reverse side effects, and decrease patient satisfaction. Furthermore, use and abuse of opioids have contributed to an opioid epidemic, especially in the United States since the beginning of the twenty-first century. Opioid-free anesthesia is an alternative aimed at providing pain relief without the opioid-related adverse effects and to enhance recovery. Non-opioid alternatives and preoperative patient education strategies have been shown to be superior in the management of postoperative pain and opioid requirements. Clinicals have embraced these concepts enthusiastically and have begun to incorporate an opioid-free pain management approach in surgery

FLOWERS FROM THE DEVIL: AN AMERICAN OPIATE CRISIS, THE CRIMINALIZATION OF MARIJUANA, AND THE TRIUMPH OF THE PROHIBITION STATE, 1840-1940

This dissertation focuses on historic changes in public perception of narcotic use and abuse from the mid-nineteenth century to the mid-twentieth. From the 1840s to the outbreak of Civil War, politicians, physicians, the general public, and state and federal government remained largely ambivalent on the topic of drug use. Opium, morphine, and cannabis were legal, widely available in American pharmacies, and touted as essential medicines. Within the Bohemian community, artists and writers experimented with the recreational use of cannabis and their accounts of that style of consumption filled the pages of Harper’s, The New Yorker, and a host of other literary-minded publications. By the 1880s, that seemingly permissive environment seemed to suddenly give way to a government increasingly focused on the regulation and prohibition of drugs. This work argues that a late-nineteenth century opiate epidemic radically transformed the country’s relationship with drugs and placed cannabis on a historical trajectory that led to its criminalization in the late-1930s. As newspapers blamed the perceived narcotic crisis that emerged in post-bellum America on the medical community, public opinion turned, to a large extent, against doctors and pharmacists. This erosion in public trust in the practice of medicine— a direct byproduct of an American opiate crisis—instigated a transfer of control over the nation’s approach to drug management. Once entirely the occupation of a relatively decentralized medical community, crucial choices over the dispensation of narcotics and their general management shifted to the arena of popular politics. This dissertation argues that transference of power aided the formation of a prohibition-minded state that rapidly banned smokable opium, non-medicinal opiates, cocaine, alcohol, heroin, and—eventually—marijuana

Role of serotonin in central dopamine dysfunction

The interaction between serotonin (5-HT) and dopamine (DA)-containing neurons in the brain is a research topic that has raised the interest of many scientists working in the field of neuroscience since the first demonstration of the presence of monoamine-containing neurons in the mid 1960. The bulk of neuroanatomical data available clearly indicate that DA-containing neurons in the brain receive a prominent innervation from serotonin (5-hydroxytryptamine, 5-HT) originating in the raphe nuclei of the brainstem. Compelling electrophysiological and neurochemical data show that 5-HT can exert complex effects on the activity of midbrain DA neurons mediated by its various receptor subtypes. The main control seems to be inhibitory, this effect being more marked in the mesocorticolimbic DA system as compared to the DA nigrostriatal system. In spite of a direct effect of 5-HT by its receptors located on DA cells, 5-HT can modulate their activity indirectly, modifying γ-aminobutyric (GABA)-ergic and glutamatergic input to the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Although 5-HT/DA interaction in the brain has been extensively studied, much work remains to be done to clarify this issue. The recent development of subtype-selective ligands for 5-HT receptors will not only allow a detailed understanding of this interaction but also will lead to the development of new treatment strategies, appropriate for those neuropsychiatric disorders in which an alteration of the 5-HT/DA balance is supposed.peer-reviewe

Mechanisms of drug addiction: focus on positive reinforcing properties of morphine

http://www.ester.ee/record=b1053314~S1*es

Pharmakon in the Firelands: Connecting Historical Discourses and Small-Town Social Contexts with Substance Use Experience

The ongoing increase in opioid and polysubstance-related overdoses and mortality in United States coincides with a shift in the ways substance use is understood. Once almost exclusively treated as a criminal problem, substance use, and overdose is increasingly viewed in terms of public health and from an urban to rural issue. The discourse surrounding the use of psychoactive substances largely omits the voices of the very people who use them. Likewise, the social context of small towns, at once not quite rural nor entirely urban, is generally given little consideration. To address these gaps in the research, I conduct two historical discourse analyses; the first analyzing advertisements and the second studying news articles published in the Northern Ohio region known as The Firelands. I conduct and analyze unstructured interviews with current and former opioid and polysubstance users, their family, and friends. I employ ethnographic data collection to advance and enrich the sociological understanding of the lived experiences and knowledge of the people who use psychoactive substances. The results of the discourse analysis are used to contextualize the knowledge of small-town opioid users and their lived experiences. Collectively, these insights contribute to the sociological study of deviance, a deeper understanding of drug use within the context of space and place, and the sociology of health and medicine

DISCOVERY OF NOVEL PHARMACOTHERAPEUTICS FOR SUBSTANCE USE DISORDERS

Substance use disorders are serious health concerns in the United States. Furthermore, the National Survey on Drug Use and Health reports a continuous increase in substance use disorders in the United States during the last 10 years. However, there are not many effective pharmacotherapeutics available for substance use disorders. The current dissertation is focused on research aimed at discovering pharmacotherapeutics for substance use disorders. First part of dissertation focused on discovering methamphetamine (METH) use disorder therapeutics targeting specific mechanism of METH action on dopaminergic neurons. The second part of dissertation focused on opioids and cocaine use disorder therapeutics targeting rewarding pathway commonly activated by opioids and cocaine. With respect to METH, it induces release of dopamine (DA) in neuronal terminals by interacting with the vesicular monoamine transporter-2 (VMAT2) and DA transporter (DAT). VMAT2 inhibitors have been found by our research group to decrease METH-evoked DA release, METH-induced hyperlocomotion, and METH self-administration in rats. However, these VMAT2 inhibitors lacked selectivity and tolerance developed to these pharmacologic effects after repeated administration, thereby limiting their potential as pharmacotherapeutics for METH use disorders. In the current study, analogs from a novel scaffold were found to selectively inhibit VMAT2 and were evaluated using neurochemical and behavioral pharmacological approaches. R- and S-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11610 and GZ-11608, respectively) exhibited 94- to 3450-fold selectivity for VMAT2 over human-ether-a-go-go (hERG) channel, DAT, serotonin transporter, and nicotinic acetylcholine receptors. GZ-11608 competitively and concentration-dependently inhibited METH-evoked DA release via VMAT2. Also, GZ-11610 (56-300 mg/kg, oral) and GZ-11608 (300 mg/kg, oral; 10-30 mg/kg, s.c.) reduced METH-induced hyperlocomotor activity in METH-sensitized rats. Furthermore, GZ-11608 (1-30 mg/kg, s.c.) inhibited METH self-administration, cue- and METH-induced reinstatement in a dose-dependent manner, and 30 mg/kg (s.c.), 10 mg/kg (s.c.), and 17 mg/kg (s.c.) produced significant effect, respectively. Importantly, the GZ-11608-induced decrease in METH self-administration was not surmounted by increasing the amount of METH available. GZ-11608 did not substitute for METH and did not serve as a reinforcer in rats self-administering METH and drug naïve rats, respectively. Thus, these VMAT2 inhibitors incorporating a new scaffold are novel leads for new pharmacotherapeutics to treat METH use disorders. Substances with high abuse potential including opioids and cocaine elevate extracellular DA concentration in the nucleus accumbens, and this mechanism has long been considered to underly substance-induced reward. DA in the nucleus accumbens originates from DA neuron cell bodies located in the ventral tegmental area in the midbrain. Interestingly, M5 muscarinic acetylcholine receptors (mAChRs) are proteins that are highly expressed on ventral tegmental area DA neurons. Also, studies investigating M5 mAChRs knockout mice showed reduced responding for cocaine in cocaine self-administration and decreased time spent in cocaine-paired and morphine-paired place preference studies. Pharmacological inhibition of M5 mAChRs function via microinfusing mAChR antagonists exhibiting no selectivity among M1-M5 mAChRs subtypes into the ventral tegmental area where expression of M5 mAChRs are dominant, reduced morphine-induced hyperlocomotion and cocaine seeking behaviors in rats. These studies support therapeutic potential of M5 mAChRs selectivity antagonists in opioids and cocaine use disorders. Thus, in the current study, affinity of a series of pethidine and quinuclidinyl N-phenylcarbamate analogs for M5 mAChRs was evaluated using in vitro and ex vivo neuropharmacological assays. Among the pethidine analogs, compound 6a showed the highest binding affinity at M5 (Ki = 0.38 µM), but also high affinity at M1 and M3 mAChRs (0.67 and 0.37 µM, respectively). Among the quinuclidinyl N-phenylcarbamate analogs, compound 13c exhibited the highest affinity at M5 (Ki = 1.8 nM), but also high affinity at M1, M2, M3 and M4 mAChRs (Ki = 1.6, 13, 2.6, 2.2 nM, respectively). Also, 13c acted as an agonist of mAChRs on oxotremorine-induced DA release from rat striatal slices. In addition, compound 13b was found exhibiting the highest selectivity (17-fold) at M3 over M2 mAChRs, suggesting potential of 13b as a chronic obstructive pulmonary disease therapeutics. Taken together, these novel analogs serve as leads for further discovery of subtype-selective M5 mAChR antagonists that may have potential as therapeutics for substance use disorders, as well as for chronic obstructive pulmonary disease