The literature relating to the ontogeny of the opioid system and to the toxic effects of lead in both man and animals with particular reference to neurochemical and behavioural toxicity of lead is reviewed. The effects of perinatal lead exposure on the development of several aspects of opioid function has been studied using a dosing model of lead (as the acetate) in the maternal drinking water from conception until postnatal day 14 or 21. This model of low level perinatal lead exposure in rats had no toxic effects on growth and produced blood lead levels close to the safety limits set for human exposure and similar to those that have been recorded in some children. The ontogeny of morphine antinociception using the tail immersion test and ketocyclazocine in the paw pressure test was studied in 10,21 and 30 day old rats. Perinatal lead exposure decreased the antinociceptive activity of both morphine and ketocyclazocine in 10 day old rats. Recovery of morphine antinociception occured by 21 days and ketocyclazocine antinociception by 30 days. Radioligand binding studies with [3H]DAGO were used to study the ontogeny of u-opioid receptors in 10,21 and 30 day old rats. Perinatal lead exposure was without effect on equilibrium dissociation constant or maximal binding capacity. Radioligand binding studies with [[3]H] DPDPE were used to study the ontogeny of 6 -opioid receptors in rats between 15 and 50 days. The affinity of the 6-opioid binding site for [[3]H] DPDPE was reduced by perinatal lead exposure but without accompanying changes in binding capacity. This effect of lead on s-opioid receptors was persistant and was observed in rats aged 15-50 days. Basal plasma corticosterone levels (measured fluorimetrically) were elevated by perinatal lead exposure in 45 and 60 day old rats but not in 30 day old rats. In addition the modulatory effect of morphine on stress induced elevations of corticosterone levels was also affected by lead exposure. A reduced effect of morphine was seen in 30 day old animals whilst an increased effect was seen in 60 day old animals. Locomotor activity (measured by photocell detection) of 10,21 and 30 day old rats was recorded over 1 hour during the dark phase of the light/dark cycle. Exploratory locomotor activity was reduced in lead exposed animals at postnatal day 10 and the hypolocomotor effect of morphine was also increased in 10 day old lead exposed animals. The opioid system is particularly sensitive to perinatal low level lead exposure and this is manifested in several aspects of physiological function. Possible mechanisms by which lead affects the development of the opioid system are discussed.

Accumulating evidence suggests a prominent role of the arrestin-dependent signaling pathway in triggering most of the deleterious side effects observed using δ-OR targeting drugs. Numerous small molecules targeting the δ-OR receptors have been developed but their pharmacological properties, including their functional selectivity, have been poorly characterized. The absence of functionally selective opioid drugs, and the lack of knowledge of the pharmacological profile and signaling properties of the δ-OR receptor, limits its therapeutic exploitation. The development of functionally selective modulator toward the canonical G protein pathway could importantly increase the therapeutic potential of this receptor while decreasing its deleterious effects. An approach to fine-tune the functional selectivity of a GPCR is by using allosteric modulators. These allosteric modulators would reduce problems associated with drugs targeting the orthosteric site by not chronically activating the receptor. The overall goal of the proposed research is to study the molecular mechanism by which sodium-channel inhibitors allosterically regulates the delta opioid receptor (δ-OR) signaling and functional selectivity. Additionally, the signaling features of the δ-OR signal transduction triggered by biased receptor activation have been investigated. A combination of approaches, including functional studies, molecular modeling and mutagenesis, were used to study the general mechanism underlying the activation and tuning of the δ-OR signal transduction behavior. Thus, this work suggests the druggability of the allosteric sodium pocket by using sodium channel inhibitors. The current research represent discovery of two different allosteric profiles for the β-arrestin recruitment and one allosteric profile for the G-protein pathway at activated DOR and would serve as scaffold for further refinement of modulators with the desired pharmacological profile.

The opioid crisis has reached unprecedented levels with the rise in deaths rising fivefold from 2001. The crisis’ has effected many communities throughout the United States and requires deep intervention in order to minimize the number of individuals dying from opioids. The heart of the problem lies in prescription opioids and heroin, one cannot talk about prescription opioids without speaking of the dangers of heroin. The purpose of this thesis is to examine the results of state and federal policies in handling the epidemic and recognizing the need for a comprehensive, multi-tiered strategy for grappling with the crisis. This paper was divided into four sections: The Nature of the Problem, Education, Supply Reduction and Treatment of Addicts and Death Prevention. The results were compiled by analyzing government statistics and peer-reviewed journals for solutions to the larger questions of how did the epidemic start, what methods can minimize illicit drug use and how do we restrict the supply of prescription opioids and heroin effectively while creating accessible treatment for individuals suffering from pain and/or addiction? The results concluded that creating educational programs based around the dangers of opioids and treatment options, while not definitive, can reduce the number of individuals suffering from addiction by allowing them to abstain from illicit drug use. This requires an immense number of state and federal resources to be dedicated to the epidemic, but considering that thousands are dying from it every year, there needs to considerable funding, energy and effort expended on grappling with the crisis.

This diploma thesis deals with preparation of modified ligands of mu, delta and kappa opioid receptors, following up on the author's bachelor's thesis.1 The main goal of the submitted thesis is ligand tethering at an appropriate position using oligoethylene glycol linkers, to enable their use in the innovative iBodies concept.2 Ligands chosen for modifications were: naltrexone (μ-opioid receptor), naltrindole (δ-opioid receptor) and nalfurafine (κ-opioid receptor). Naltrexone was modified, according to the bachelor's thesis results, at the C-6 position with linker attachment via ether and amide. At the same time, the influence of the configuration at the newly formed C-6 stereogenic center on biological activity was studied. In case of naltrindole, access through indole nitrogen was chosen based on the information in literature.3-5 Nalfurafine was modified on the furane fragment. Series of fluorescently labeled ligands were prepared. Attachment of the fluorescent tag allowed us to study the affinity and selectivity of these modified ligands. Based on the results, ligands for development of DIANA method and for preparation of synthetic iBodies were synthesised.6 Key words: naltrexone, receptor, conjugate, opioid receptor 1 M. Hadzima. Fluorescenčně značené ligandy μ-opioidních receptorů, 2016. 2 P....

Orientador: Claudia Herrera Tambeli / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-20T01:36:46Z (GMT). No. of bitstreams: 1 Macedo_CristinaGomesde_M.pdf: 777542 bytes, checksum: 9fba5bed6fd851b4349bf4812dda8d33 (MD5) Previous issue date: 2012 / Resumo: Disfunções temporomandibulares são condições dolorosas que envolvem a articulação temporomandibular e os músculos mastigatórios com maior prevalência, severidade e duração no sexo feminino. Recentemente foi demonstrado que a testosterona apresenta um efeito protetor ao diminuir o risco de ratos desenvolverem dor na Articulação Temporomandibular (ATM), o que explica pelo menos em parte, a menor prevalência de dor no sexo masculino. No entanto, o mecanismo através do qual a testosterona induz o efeito protetor em machos não é conhecido. Assim, o objetivo deste trabalho foi investigar se o efeito protetor da testosterona é mediado pela ativação do sistema opióide endógeno no sistema nervoso central e quais os subtipos de receptores opióides estão envolvidos nesse efeito protetor sobre o desenvolvimento de dor na ATM em ratos. Para o procedimento experimental foram usados ratos machos Wistar (230-300 g), intactos, gonadectomizados (Gx) e sham gonadectomizados (sham Gx) e a injeção de formalina 0,5% na ATM foi usada como estímulo nociceptivo. Para testar o envolvimento de um mecanismo neural central dependente da ativação do sistema opióide, os animais receberam injeção de naloxona, antagonista não seletivo de receptores opióides, CTOP, Naltrindole e Nor-BNI, antagonistas opióides seletivos para os subtipos de receptores opióides mu (µ ), delta e capa (µ ), respectivamente na região do núcleo sensorial trigeminal, antes do teste da formalina na ATM. A administração da Naloxona (15?g) antagonista não seletivo ou a combinação dos antagonistas de receptor µ opióide CTOP (30µ g/10µ l) mais o de receptor µ opióide Nor- BNI (90µ g/10µ l) aumentou significativamente a nocicepção induzida pela formalina 0,5% na ATM em ratos sham Gx, mas não em ratos Gx (31.09%, n = 6 e 26,9%, n = 6; respectivamente) A resposta de ratos intactos a estes tratamentos foi semelhante à de ratos sham Gx. Em contraste, a administração de cada antagonista de receptores opióides sozinhos ou a combinação de CTOP (30µ g/10µ l) mais o antagonista do receptor delta opióide Naltrindole (90µ g/10µ l) ou de Nor-BNI (90µ g/10µ l) mais Naltrindole (90µ g/10µ l) não afetou a nocicepção induzida pela formalina 0,5% em ratos Gx, intactos e sham Gx. Estes resultados sugerem que o efeito protetor da testosterona no desenvolvimento da dor na ATM depende da liberação de opióides endógenos e a subseqüente ativação dos receptores opióides mu e capa no sistema nervoso central. Conclui-se que a ativação individual dos subtipos de receptores é insuficiente enquanto que a co-ativação dos receptores opióides µ e k é necessária para mediar o efeito protetor da testosterona / Abstract: Temporomandibular Joints (TMJ) dysfunctions are painful conditions involving the masticatory muscles and temporomandibular joint with higher prevalence, severity and duration in females. Recently it was shown that testosterone has a protective effect by reducing the risk of rat develop pain in TMJ, which explains at least in part, the lower prevalence of pain in males. However, the mechanism through which the testosterone induces protective effect in males is not known. Thus, the aim of this study was to investigate whether the protective effect of testosterone is mediated by activation of endogenous opioid system in the central nervous system and what subtypes of opioid receptors are involved in this protective effect on the development of TMJ pain in rats. For the experimental procedure Intact, gonadectomized and sham Wistar (230-300g) male rats were used and all experimental procedures were approved by the Ethics Committee in Animal Research at the UNICAMP. The TMJ injection of 0.5% formalin was used as a nociceptive stimulus. The nociceptive behavior was quantified for 45 minutes and used as a quantitative nociceptive behavior measure that was defined as the cumulative total number of seconds that the animal spent rubbing the orofacial region asymmetrically with the ipsilateral fore or hind paw plus the number of head flinches counted during the observation period. Administration of the opioid receptor antagonist naloxone 15 mg or the combination of the mu-opioid receptor antagonists CTOP (30µ g/10µ l) plus the kappa-opioid receptor antagonist nor-binaltorphimine (90µ g/10µ l), significantly increased TMJ 0.5% formalin-induced nociception in sham (31.09%, n=6 and 26.9%, n=6; respectively) but not in gonadectomized rats. The response of intact rats to these treatments was similar to that of sham rats. In contrast, the administration of each opioid receptor antagonist alone or the combination of CTOP (30µg/10µ l) plus the delta-opioid receptor antagonist Naltrindole (90µ g/10µ l) or of Nor-binaltorphimine (90µ g/10µ l) plus Naltrindole (90µ g/10µ l) did not affect TMJ 0.5% formalin-induced nociception in intact, sham and gonadectomized rats. These findings suggest that the protective effect of testosterone on TMJ pain development depends on the release of endogenous opioids and on the subsequent activation of mu and kappa opioid receptors in the central nervous system. The conclusion is that the selective activation of individual receptor subtypes is insufficient while the co-activation of µ and k opioid receptors is necessary to mediate the protective effect of testosterone / Mestrado / Fisiologia Oral / Mestre em Odontologia

Chronic neuropathic pain is a disease that impacts the livelihood of millions of people in the United States with no effective pain treatments and limited information pertaining to the underlying mechanisms. Opioid therapy is considered the gold standard for pain therapeutics, but chronic use of these medications brings about serious side effects such as tolerance, addiction, and respiratory depression which limit their overall therapeutic potential. Herein, two approaches are discussed to circumvent these issues: i) a multifunctional approach using N-phenyl-N-piperidin-4-yl-propionamide (Ppp) coupled to various endogenous opioid ligand scaffolds, and ii) non-opioid dynorphin A (DYN A) ligands at the Bradykinin-2 receptor (B2R). The μ-opioid receptor (MOR) upon agonist stimulation provides analgesia and concomitant activation of the δ-opioid receptor (DOR) leads to an increased antinociceptive effect. Chronic activation of the MOR has been correlated with an upregulation of the κ-opioid receptor (KOR) and KOR associated side effects such as anxiety and depression. The discovery of a new class of opioid receptor (OR) ligands that have the biological profile of MOR/DOR agonists and KOR antagonists would be beneficial considering they would have an increased analgesic effect, leading to a lower dosage being administered and thus lower overall side effects, and block symptoms elicited from KOR stimulation. Discussed are various structure activity relationships (SARs) of numerous scaffolds that present novel biological profiles. Ultimately, we discovered a compound that, to our knowledge, is the 1st MOR/DOR agonist and KOR antagonist. DYN A is the endogenous ligand for the KOR and its [des-Tyr1]-DYN A fragment interacts with the B2R, but not the KOR, promoting hyperalgesia. Peptidomimetic non-opioid DYN A analogues were synthesized and evaluated at the B2R. A minimum pharmacophore was identified and antagonists with both improved biological stability and affinity were discovered.

Class of 2014 Abstract / Specific Aims: To show that Suboxone is more effective than no MAT (Medically Assisted Treatment) in opioid dependence. Additionally, that Suboxone is as effective as methadone in MAT. Methods: This study was a retrospective chart review of probationer’s case files at The Pima County Adult Probation Office. Treatment groups included: Suboxone (n=16), methadone (n=15), and no MAT control group (n=15). The total sample size was 46 probationers. The primary dependent variables were the number of negative events and time to a negative event (i.e. missed/positive urinalysis, violation of terms of probation). The secondary outcome variables were the number of positive events and time to a positive event (i.e. finding employment, documented social/family improvement). Data analysis utilized chi-square for categorical data while t-tests were used for continuous data. Main Results: 46 probationers of Pima County with violations related to possession or use of an opioid substance were analyzed. No significant differences were found between Suboxone and placebo (no MAT) for any of the four outcomes (number of negative events p=0.82; time to first negative event p=0.41; number of positive events p=0.93; time to first positive event p=0.45). No significant differences were found between Suboxone and methadone as well (number of negative events p=0.34; time to first negative event p=0.52; number of positive events p=0.93; time to first positive event p=0.56). Conclusion: This study found no statistically significant differences between no MAT and Suboxone nor Suboxone and methadone. Differences in baseline characteristics between groups were found that could characterize the Suboxone group as being more severely ill.

Class of 2015 Abstract / Objectives: Evaluate prescriber knowledge on naloxone use for opioid overdose reversals in intravenous drug users. Interview prescribers on their perceptions about intravenous drug users, syringe access programs, and other related topics. Subjects: Prescribers and medical professionals in the State of Arizona. Methods: Medical facilities were contacted by email, fax, or telephone requesting for prescribers to complete the survey and return by email or fax, or call to schedule a face-to-face appointment. The respondents of the survey were kept anonymous and were permitted to answer the survey in free text. Surveys were sent to the 68 selected medical facilities at least twice during the study period. Results: All of the six respondents were male, of the respondents had at least 11 years experience, with two having >30 years. A majority practiced in rehab centers or worked with drug abuse patients, however the number of patients treated per week by respondent varies from 10-320. Also of note five of the six respondents had a family member or relative with an addiction to opioids. The respondents seem to be in support of a naloxone distribution program however it is difficult to draw any conclusions since the number of responses was low. Conclusions: It appears that prescribers have a favorable perception of naloxone use and support harm reduction strategies, however response rate was too low to make any definitive conclusions.

The present study aimed at quantifying the topographic distribution of spectral power as measured with electroencephalogram (EEG) in patients with opioid use disorder (OUD) across five broad band frequencies (δ, θ, α, β, and γ). Through comparative groups of healthy controls, patients with methamphetamine use disorder, and patients with alcohol use disorder, it was determined that OUD EEG spectral power was globally increased in the δ frequency, and more region-specific in others (frontal lobes in θ and β frequencies). α frequency was reduced in occipital lobes in OUD. The observed changes are discussed in terms of the microcircuit-level changes in the cortex. Based on these findings, EEG may prove to be a valuable tool for diagnostic and prognostic evaluation of OUD. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2020. / FAU Electronic Theses and Dissertations Collection

Orientador: Guilherme Antonio Moreira de Barros / Resumo: Introdução: A dor é uma experiência pessoal, subjetiva, que envolve aspectos sensitivos e culturais que podem ser alterados pelas variáveis socioculturais e psíquicas do indivíduo, do meio e, apesar de classificações diversas, geralmente relacionada ao sofrimento. No Brasil estudos indicam que, embora cerca de 50% dos pacientes portadores de dor estejam medicados, a maior parte deles está descontente com os resultados do tratamento. Em situação de dor aguda traumática, apenas 7% dos pacientes tem suas dores totalmente aliviadas e, em pacientes em vigência de dor de intensidade moderada a grande, somente 25% receberam opioides como parte de seu tratamento, apesar de recomendação da OMS de uso destes analgésicos, como descrito na escada analgésica. Objetivo: Compreender as razões da baixa prescrição dos opioides no tratamento da dor no Brasil, com ênfase aos entraves sociais, legais e burocráticos existentes. Métodos: Trata-se de um estudo epidemiológico, prospectivo, analítico observacional e transversal, aprovado pela Comissão de Ética em Pesquisa, e realizado a partir de questionário investigativo disponibilizado em plataforma online, com perguntas fechadas e abordagem quantitativa. Foram convidados a participarem do estudo, por meio de mensagens eletrônicas a médicos atuantes em território Nacional. Aqueles que concordaram em participar assinaram, eletronicamente, o Termo de Consentimento Livre e Esclarecido (TCLE) online. Para análise estatística foram realizados os teste... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Pain is a personal, subjective experience, involving sensitive and cultural aspects that can be altered by the socio-cultural and psychological variables of the individual, the environment and, despite different classifications, it is frequently related to suffering. In Brazil studies indicate that, although about 50% of pain patients are medicated, most of them are unhappy with the treatment outcomes. In situations of acute traumatic pain, only 7% of patients have their pain totally relieved and, in patients with moderate to severe pain, only 25% received opioids as part of their treatment, despite of the WHO recommendation to use these analgesics, as described on the analgesic ladder. Objective: To understand the reasons for the low prescription of opioids in the treatment of pain in Brazil, with emphasis on the existing social, legal and bureaucratic barriers. Method: This is a prospective, observational and cross-sectional epidemiological study, approved by the Research Ethics Committee, and carried out using an investigative questionnaire available on an online platform, with closed questions and a quantitative approach. Participants were invited to participate in the study, through electronic messages to medical doctors working in the national territory. Those who agreed to participate signed, electronically, the Free and Informed Consent Term (ICF) online. For statistical analysis, chi-square tests were performed followed by Z tests and Student's t tests.... (Complete abstract click electronic access below) / Doutor