The aims of the thesis were to examine i) whether the endogenous opioid system (EOS) is lateralized in human brain areas involved in processing of emotions and pain; ii) whether EOS responses to unilateral brain injury depend on side of lesion, and iii) whether in human alcoholics, this system is involved in molecular adaptations in brain areas relevant for cognitive control of addictive behavior and habit formation. The main findings were that (1) opioid peptides but not opioid receptors and classic neurotransmitters are markedly lateralized in the anterior cingulate cortex involved in processing of  positive and negative emotions and affective component of pain. The region-specific lateralization of neuronal networks expressing opioid peptides may underlie in part lateralization of higher functions in the human brain including emotions and pain. (2) Analysis of the effects of traumatic brain injury (TBI) demonstrated predominant alteration of dynorphin levels in the hippocampus ipsilateral to the injury, while injury to the right hemisphere affected dynorphin levels in the striatum and frontal cortex to a greater extent than that to the left hemisphere. Thus, trauma reveals a lateralization in the mechanisms mediating the response of dynorphin expressing neuronal networks in the brain. These networks may differentially mediate effects of left or right brain injury on lateralized brain functions. (3) In human alcoholics, the enkephalin and dynorphin systems were found to be downregulated in the caudate nucleus and / or putamen that may underlie in part changes in goal directed behavior and formation of a compulsive habit in alcoholics. In contrast to downregulation in these areas, PDYN mRNA and dynorphins in dorsolateral prefrontal cortex, k-opioid receptor mRNA in orbitofrontal cortex, and dynorphins in hippocampus were upregulated in alcoholics. Activation of the k-opioid receptor by upregulated dynorphins may underlie in part neurocognitive dysfunctions relevant for addiction and disrupted inhibitory control. We conclude that the EOS exhibits region-specific lateralization in human brain and brain-area specific lateralized response after unilateral TBI in mice; and that the EOS is involved in adaptive processes associated with specific aspects of alcohol dependence.

While the classical function of myelin is to facilitate saltatory conduction, this membrane and the myelin-making oligodendrocytes (OLGs) are now recognized as regulators of plasticity and remodeling in the central nervous system (CNS). Thus, OLG maturation and myelination are highly vulnerable processes along CNS development. We previously showed that rat brain myelination is altered by perinatal exposure to buprenorphine, an opioid analogue in clinical trials for the treatment of pregnant opioid addicts. We now found that the in vivo effects on myelination could result from direct alteration in the balance between μ-opioid receptor (MOR) and nociceptin/orphanin FQ receptor (NOPR) activities in the OLGs. Furthermore, we found that myelination could also be affected by the FDA-approved methadone. A delicate balance between MOR and NOPR signaling may play a crucial role timing OLG maturation and myelin formation and exogenous opioids may disrupt this interplay, altering the developmental pattern of brain myelination.

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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.

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.