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Research supports that social connection is important in both humans and animals. In humans, having a cohesive support/social network system and healthy attachments in childhood predict low risk of later addiction (i.e. substance use disorder), as does perceived support from a religious or other cohesive community. Moreover, personal characteristics such as identifying as religious or spiritual can predict low risk for addiction, but little is known about the intersection of neuroscience and religion/spirituality in this regard. Conversely, adverse childhood experiences (ACEs) have repeatedly been shown to predict later addiction. However, the role of the body’s neuro-hormonal responses, such as the endogenous opioid and oxytocin systems in this process merits further exploration, such as how the production or deprivation of endogenous opioids impact later substance use patterns. Existing research also provides evidence that individuals decrease pursuit of interpersonal connections and social bonds when they use substances that activate opioid receptors. This has been found with both substances of abuse and medications used to treat addiction (e.g., methadone, buprenorphine, naltrexone). Research has also demonstrated that addiction often results in situations of social isolation. However, it remains to be elucidated whether the substances of abuse physiologically meet that need for connection. Importantly, research across numerous fields indicates that intentionally increasing interpersonal connection may be an effective treatment for addiction. However, less is known about how specific characteristics of communities impact the quantity, quality, or effectiveness of care and support for a person with addiction [...] / https://dc.etsu.edu/etsu_books/1292/thumbnail.jpg

<p>The endogenous opioid enkephalin neuropeptides are mediators of pain perception and have been implicated in human addictions. The preproenkephalin gene and its mRNA have also provided many examples of tissue- and species-specific variations in mRNA structure produced through a variety of transcriptional and post-transcriptional mechanisms. Resultant differences in mRNA structure, in several cases, have impact on translation of enkephalin prepropeptide. The reports and discussion presented herein describe studies of the preproenkephalin gene and mRNA structure in the guinea pig, an animal that may have specific advantages for modeling the human endogenous opioid system. A guinea pig brain cDNA library was constructed and screened for clones of preproenkephalin and preprodynorphin, which were then sequenced. These studies confirmed the predicted mRNA structure that had been previously proposed based on homology with gene sequences and other methods. Multiple transcription initiation sites for each of these prepropeptide genes were also identified. Studies were conducted in the guinea pig to evaluate the effects of the administration of cocaine in a “binge” paradigm for two and seven days on preproenkephalin mRNA levels in several brain regions. “Binge” cocaine administration for seven (but not two) days resulted in differential changes in mRNA levels in different brain regions. Decreases were observed in the nucleus accumbens and hypothalamus, and increases in the frontal cortex, amygdala and hippocampus. These findings differ from those of previous rodent studies and suggest that this species may provide a useful alternative model for the study of the effects of cocaine on preproenkephalin gene expression in the human brain. Human genetic studies were also conducted in opioid-dependent (formerly heroin-addicted) and control subjects to test the hypothesis that the preproenkephalin gene is associated with heroin addiction. In two separate studies, we obtained evidence that this gene may be associated with the development of human heroin addiction.</p>

The endogenous opioid enkephalin neuropeptides are mediators of pain perception and have been implicated in human addictions. The preproenkephalin gene and its mRNA have also provided many examples of tissue- and species-specific variations in mRNA structure produced through a variety of transcriptional and post-transcriptional mechanisms. Resultant differences in mRNA structure, in several cases, have impact on translation of enkephalin prepropeptide. The reports and discussion presented herein describe studies of the preproenkephalin gene and mRNA structure in the guinea pig, an animal that may have specific advantages for modeling the human endogenous opioid system. A guinea pig brain cDNA library was constructed and screened for clones of preproenkephalin and preprodynorphin, which were then sequenced. These studies confirmed the predicted mRNA structure that had been previously proposed based on homology with gene sequences and other methods. Multiple transcription initiation sites for each of these prepropeptide genes were also identified. Studies were conducted in the guinea pig to evaluate the effects of the administration of cocaine in a “binge” paradigm for two and seven days on preproenkephalin mRNA levels in several brain regions. “Binge” cocaine administration for seven (but not two) days resulted in differential changes in mRNA levels in different brain regions. Decreases were observed in the nucleus accumbens and hypothalamus, and increases in the frontal cortex, amygdala and hippocampus. These findings differ from those of previous rodent studies and suggest that this species may provide a useful alternative model for the study of the effects of cocaine on preproenkephalin gene expression in the human brain. Human genetic studies were also conducted in opioid-dependent (formerly heroin-addicted) and control subjects to test the hypothesis that the preproenkephalin gene is associated with heroin addiction. In two separate studies, we obtained evidence that this gene may be associated with the development of human heroin addiction.

Alcohol use disorder is a worldwide public health problem and is a disorder with substantial individual variation. There are suggested links between various behavioral traits, comorbid psychiatric diseases and excessive alcohol consumption. Moreover, the endogenous opioid system is involved in alcohol reward and reinforcement, and implicated in the action of alcohol. However, less is known about the complex associations between individual differences in behavior, alcohol consumption, pharmacotherapy response and related neurochemical mechanisms. Experimental animal models are critical for understanding the neurobiological underpinnings of alcohol use disorder. The overall aims of this thesis were: i) to study the association between behavior and voluntary alcohol intake in outbred rats; ii) to study the association of voluntary alcohol intake, behavior, opioid receptor density and response to naltrexone; and iii) to obtain detailed behavioral characterizations of the animals on the basis of their voluntary alcohol intake. The results revealed that the multivariate concentric square fieldTM (MCSF) test was a complementary method for understanding mechanisms underlying various mental states. The MCSF broadened the perspective on risk-related behaviors, including aspects of risk assessment. Individual differences in alcohol intake using the modified intermittent access paradigm enabled analyses of drinking patterns in high and low alcohol-drinking rats. There was an alcohol deprivation effect in high-drinking animals only. The behavior profiling of high alcohol drinking- rats before and after alcohol access suggested that this subgroup was consuming alcohol for its anxiolytic properties. Long-lasting changes were found in the mu and the delta opioid receptors after long-term, intermittent voluntary alcohol intake; some of these changes are in line with findings in humans. The voluntary alcohol consumption and the concomitant response to naltrexone were different for Wistar rats from different suppliers. Moreover, the Rcc Wistar rats may be more suitable for studies of alcohol use disorders due to increasing alcohol intake and the presence of a high-drinking subpopulation with increasing alcohol intake over time. The high-drinking subpopulation showed pronounced effects of naltrexone on alcohol intake. In conclusion, studies of individual differences increase understanding of variability in behavior, pharmacotherapy response and factors involved in vulnerability of alcohol use disorders.

α-Terpineol (TPN) is an alcoholic monoterpene present in the essential oil of oregano and thyme, having anticonvulsant, antinociceptive and anti-inflammatory properties. The TPN analgesic activity is associated with its actions in the central nervous system (CNS), what can suggest that TPN can act on dysfunctional chronic pain, such as fibromyalgia (FM). The FM is a chronic rheumatic disease with pathophysiology related to alterations in neurotransmission systems. The current therapy for FM is mainly characterized by pharmacotherapeutic conduct; however, there is significant drug resistance. Thus, the aim of this study was to evaluate the possible anti-hyperalgesic effect of an inclusion complex containing TPN and β-cyclodextrin (βCD) in the non-inflammatory chronic muscle pain model (considered to be a FM model) in rodents. The TPN-βCD complex was prepared and characterized by thermogravimetry (TG), absorption spectroscopy in the infrared Fourier transform (FTIR) and scanning electron microscopy (SEM). Albino Swiss mice were used, weighing between 20 and 30 g. The non-inflammatory chronic muscle pain model was induced by two injections of acid saline (pH 4.0 - 20 uL) into the left gastrocnemius, 5 days apart. After induction, the animals were treated with TPN-βCD (25, 50 or 100 mg/kg, p.o.), vehicle (0.9% saline, p.o.) or tramadol (5 mg/kg; i.p.) for 10 consecutive days. An hour after the treatment, it was measured the mechanical hyperalgesia through digital analgesimeter, the motor performance through the Rota-Rod and muscle strength through the Grip Strength Meter. In addition, it was tested the action of the administration of ondansetron and naloxone (opioid and serotonin antagonists, respectively) in the TPN analgesic action. The results were expressed as mean ± standard error and the differences between groups were analyzed using ANOVA followed by Tukey's test. After incorporation of TPN in βCD, the complexes were characterized physical chemically by different methods: TG, FTIR and SEM. These results together suggested the formation of TPN-βCD complex. The oral treatment with TPN-βCD, in all doses, produced a significant reduction (p <0.001) in the mechanical hyperalgesia without causing any changes in motor coordination. The muscle strength increased after the administration of the highest dose. The analgesic time effect in animals treated with TPN-βCD complex was over four hours to the free αTPN, being these difference statistically significant (p <0.01). The analgesic effect observed was reversed by systemic administration of naloxone or ondansetron. Corroborating these findings, the "docking" study confirmed the possible interaction of αTPN with opioid (mu, kappa, delta) and serotonin receptors. Thus, it can be concluded that the TPN-βCD complex reduced the mechanical hyperalgesia in the chronic muscle pain model, probably due to activation of CNS areas, possibly acting on opioid and serotonin receptors. / O α-terpineol (TPN) é um monoterpeno alcoólico presente no óleo essencial de orégano e tomilho com propriedades anticonvulsivantes, antinociceptiva e anti-inflamatória. As propriedades analgésicas do TPN estão associadas a suas ações no sistema nervoso central (SNC), sendo sugestivo seu efeito sobre dores crônicas conhecidas como disfuncionais, tais como a fibromialgia (FM). A FM é uma doença reumatológica crônica de fisiopatologia relacionada a alterações em sistemas de neurotransmissão e sua terapia atual é caracterizada principalmente pela conduta farmacoterapêutica, contudo, com significativa farmacoresistência terapêutica. Dessa forma, o objetivo do trabalho foi avaliar a possível efeito anti-hiperalgésico do complexo de inclusão contendo TPN e β-ciclodextrina (βCD) no modelo de dor muscular crônica não inflamatória (considerado ser um modelo experimental de FM) em roedores. O complexo TPN-βCD foi preparado e caracterizado por termogravimetria (TG), espectroscopia de absorção na região do infravermelho com transformada de Fourier (FTIR) e microscopia eletrônica de varredura (MEV). Foram utilizados camundongos Swiss albinos machos pesando de 20 a 30 g. O modelo de hiperalgesia muscular crônica não inflamatória foi induzida por duas injeções de solução salina (pH 4,0 - 20 μL) no gastrocnêmio esquerdo, sendo a primeira no dia 0 e a segunda no dia 5. Após a indução da hiperalgesia, os animais foram tratados com αTPN-βCD (25, 50 ou 100 mg/kg; v.o.), veículo (salina 0.9%, v.o.) ou Tramadol (4 mg/kg; i.p.) durante 10 dias consecutivos. Uma hora após analise da hiperalgesia mecânica, avaliou-se o desempenho motor no teste do Rota-Rod e a força muscular no Grip Strength Meter. Além disso, foi testado o possível antagonismo da ação analgésica pela administração de naloxona e ondansetrona (antagonistas de receptores opióides e serotoninergico, respectivamente). Os resultados foram expressos como média ± erro padrão da média e as diferenças entre os grupos foram analisadas por meio do teste de variância ANOVA, seguido pós-teste de Tukey. Após incorporação do αTPN na βCD, os complexos foram caracterizados fisico-quimcamente por diferentes métodos: TG, FTIR e MEV, e o conjunto dos resultados obtidos sugerem a formação do complexo αTPN-βCD. O tratamento oral com αTPN-βCD, em todas as doses testadas, produziu uma redução estatisticamente significativa (p<0,001), na hiperalgesia mecânica, sem causar alterações na coordenação motora e aumentando a força muscular na maior dose testada. A duração do efeito analgésico nos animais tratados com complexo αTPN-βCD foi quarto horas superior ao tempo de analgesia causada pela αTPN livre, diferença estatisticamente significativa quanto a comparação desses dois grupos (p<0,01). O efeito analgésico foi revertido pela administração sistêmica de naloxona ou ondansetrona. Corroborando com esses resultados, o estudo de “docking” confirmou a possível interação do αTPN com receptores Opióides (MU, Kappa, Delta) e Serotonina. Assim, pode-se concluir que o complexo αTPN-βCD reduziu a hiperalgesia mecânica no modelo de nocicepção muscular crônica, provavelmente por ativação de áreas do SNC, agindo, possivelmente, nos receptores opióides e serotoninérgicos.

Indiana University-Purdue University Indianapolis (IUPUI) / Naltrexone (NTX) is clinically efficacious at attenuating alcohol intake in non-abstinent alcoholics and, to a lesser extent, craving, independent of intake. While generally regarded as a non-selective opioid antagonist, NTX has been shown to have concentration dependent selectivity with lower doses (< 1.0 mg/kg) selective for the mu receptor and doses exceeding 1.0 mg/kg capable of binding to delta and kappa receptors. Like the mu system, the delta receptor system has also been implicated in mediating the rewarding effects of EtOH. In contrast, the role of the kappa system is less clear though recent evidence suggests that kappa activation may mediate EtOH aversion. Thus, the present study sought to evaluate the effects of both mu-selective and non-selective doses of naltrexone, the selective delta antagonist naltrindole (NTI), and the selective kappa agonist U50,488H (U50) in a paradigm that procedurally separates the motivation to seek versus consume a reinforcer to assess whether these receptor-selective drugs differentially affects these behaviors in both selected (alcohol-preferring P rats) and non-selected (Long Evans) rats, and whether these effects are specific to EtOH. Rats were trained to complete a single response requirement that resulted in access to either 2% sucrose or 10% EtOH for a 20-min drinking session. In three separate experiments, rats were injected (using a balanced design) with either vehicle or 1 of 3 doses of drug: U50 (IP; 2.5, 5.0, or 10.0mg/kg), NTI (IP; 2.5, 5.0, or 10.0 mg/kg), low NTX (SC; 0.1, 0.3, or 1.0 mg/kg) or high NTX (SC; 1.0, 3.0, or 10.0 mg/kg) on both consummatory and appetitive treatment days. Following either a 20 (U50), 15 (NTI), or 30 minute (NTX) pretreatment, rats were placed into an operant chamber and intake (consummatory) or lever responses (appetitive) and response latencies were recorded. The results showed that overall: U50, NTI, and NTX attenuated intake and responding for sucrose and EtOH. Independent of reinforcer, LE rats were more sensitive to U50’s effects on intake while P rats were more sensitive to the effects on seeking. P rats reinforced with EtOH were more sensitive to NTI’s effects on intake and seeking than all other rat groups. P rats were more sensitive overall to lower doses of NTX than LE rats and lower doses of NTX were more selective in attenuating EtOH responding vs. sucrose. Higher doses of NTX suppressed intake and responding across both lines and reinforcers. These results demonstrate that craving and intake may be differentially regulated by the kappa, delta, and mu opioid receptor systems as a function of “family history” and suggest that different mechanisms of the same (opioid) system may differentially affect craving and intake.

Résumé confidentiel / Résumé confidentiel

<p>In this study, we have addressed the serotonergic and the opioid system within the CNS. Both systems are of outmost importance in the etiology of disease states, especially mental disorders. </p><p>In our investigation of the serotonergic system, we have synthesized novel enantiomerically pure 6-aryl-3-amino- and 8-aryl-3-aminochromans as ligands for the 5-HT₇ receptor. One reason for the lack of understanding of the physiological functionality of the serotonin 5-HT₇ receptor, the most recently discovered member of the serotonin receptor family, is the absence of partial agonists and agonists. In this series, we have identified partial agonists with more than189 fold selectivity over the 5-HT_1Areceptor and one agonist with 29 fold greater selectivity over the serotonin 5-HT_1Areceptor. Thus the present series constitutes a starting point for developing highly selective ligands for the 5-HT₇ receptor. </p><p>In our investigation of the opioid system, our focus has been on the natural product salvinorin A, which is a highly selective kappa opioid receptor agonist. In the total synthesis of salvinorin A, we have accomplished the synthesis of a key intermediate, 6-(3-furyl)-4-methyl-5,6-dihydro-pyran-2-one via ring closing metathesis. Furthermore, synthetic methodologies have been developed as a part of the total synthesis. Several lipases have been screeened for their ability to generate enantiomerically pure 1-(3-Furyl)-3-buten-1-ol via bio-catalyzed hydrolysis of the corresponding acetate. The lipase from <i>Pseudomonas fluorescens</i> was identified as having stereoselectivity high enough to generate a % <i>ee </i>value above 98%. We have also developed a route for the introduction of a hydroxyl functionality in the γ position of α,β-unsaturated cyclic ketones by the regioselective oxidation of 1-silyloxy-1,3-dienes using dimethyldioxirane. We have initiated the investigation of the pharmacophore responsible for the kappa opioid activity by synthesizing simplified analogues of salvinorin A. A synthetic route providing easy access to simplified analogues of salvinorin A have been established.</p>

In this study, we have addressed the serotonergic and the opioid system within the CNS. Both systems are of outmost importance in the etiology of disease states, especially mental disorders. In our investigation of the serotonergic system, we have synthesized novel enantiomerically pure 6-aryl-3-amino- and 8-aryl-3-aminochromans as ligands for the 5-HT7 receptor. One reason for the lack of understanding of the physiological functionality of the serotonin 5-HT7 receptor, the most recently discovered member of the serotonin receptor family, is the absence of partial agonists and agonists. In this series, we have identified partial agonists with more than189 fold selectivity over the 5-HT1A receptor and one agonist with 29 fold greater selectivity over the serotonin 5-HT1A receptor. Thus the present series constitutes a starting point for developing highly selective ligands for the 5-HT7 receptor. In our investigation of the opioid system, our focus has been on the natural product salvinorin A, which is a highly selective kappa opioid receptor agonist. In the total synthesis of salvinorin A, we have accomplished the synthesis of a key intermediate, 6-(3-furyl)-4-methyl-5,6-dihydro-pyran-2-one via ring closing metathesis. Furthermore, synthetic methodologies have been developed as a part of the total synthesis. Several lipases have been screeened for their ability to generate enantiomerically pure 1-(3-Furyl)-3-buten-1-ol via bio-catalyzed hydrolysis of the corresponding acetate. The lipase from Pseudomonas fluorescens was identified as having stereoselectivity high enough to generate a % ee value above 98%. We have also developed a route for the introduction of a hydroxyl functionality in the γ position of α,β-unsaturated cyclic ketones by the regioselective oxidation of 1-silyloxy-1,3-dienes using dimethyldioxirane. We have initiated the investigation of the pharmacophore responsible for the kappa opioid activity by synthesizing simplified analogues of salvinorin A. A synthetic route providing easy access to simplified analogues of salvinorin A have been established.