Identification of maternal opioid abuse in pregnancy is often difficult to ascertain in the absence of reliable self report. For this reason, physicians and child protection workers often turn to maternal and neonatal hair analysis for the detection of in utero opioid exposures. Since neonatal opiate hair analysis continues to prove difficult due to the scarcity of the hair sample and low drug concentrations, I developed a sensitive method utilizing headspace solid-phase microextraction (HS-SPME) coupled with gas chromatography-mass spectrometry (GC-MS) for the detection of three principal opiates (morphine, codeine, and 6-monoacetylmorphine) in human hair. Moreover, I characterized an at-risk neonatal population for in utero opiate exposures as well as for other drugs of abuse and alcohol. Equipped with a sensitive and specific method for the detection of opiate exposures and understanding the addiction profiles of pregnant women may lead to better clinical and social management and may benefit an at-risk population.

Thesis (doctoral)--Universiẗat, Marburg, 2004.

A simple method for IV self-administration of drugs by mice is described. When morphine (0.5 mg/kg) was made contingent on a nosepoke response, naive mice increased their rate of nosepoking when compared either with animals receiving contingent saline vehicle injectionsor yoked control animals receiving noncontingent morphine.

TOPIC. Despite substantive advances in understanding of genetic and biochemical basis of substance abuse and addiction in the last decade, little information has been translated into alternative treatment models for the addicted patient. Rapid detox, an alternative form of detox treatment, is gaining in both acceptance and popularity. PURPOSE. To increase readers' understanding of the neurobiology of addiction and the mode of action of new detox approaches for patients addicted to opiate drugs. SOURCES. A review of the current literature pertaining to rapid detox. CONCLUSIONS. Rapid detox is a viable alternative for selected patients attempting to detox from opiate agents of abuse. Increasing knowledge of new treatment approaches allows nurses working to assist addicted patients in planning and receiving treatment based on new awareness of the neurobiology of addiction.

No / The pro-opiomelanocortin (POMC)-derived peptides, -melanocyte-stimulating hormone, and adrenocorticotropic hormone, are important mediators of human skin pigmentation via action at the melanocortin-1 receptor. Recent data suggests that such a regulatory role also exists for the endogenous opiate, -endorphin (-END). A role for this -END in the regulation of follicular pigmentation, however, has not been determined. This study was designed to examine the involvement of the -END/-opiate receptor system in human follicular melanocyte biology. We employed RT-PCR, and immunohisto/cytochemistry and immunoelectron microscopy using -END and -opiate receptor specific antibodies and a functional role for -END was assessed by direct stimulation with the peptide. This study has demonstrated that human hair follicle melanocytes (HFM) express mRNA for the -opiate receptor and POMC. Furthermore, -END and its high affinity -opiate receptor are expressed at the protein level in glycoprotein100-positive follicular melanocytes and as a function of their anatomic location and differentiation status during the hair growth cycle. Functional studies revealed that -END is a modifier of HFM phenotype via its ability to upregulate melanogenesis, dendricity, and proliferation. These findings suggest a new regulatory role for -END in human HFM biology, providing a new research direction into the fundamental regulation of human hair pigmentation.

Endomorphin 1 (10, 30, 100 nmol/kg) administered intravenously (i.v.) to urethane-anesthetized rats consistently and dose-dependently lowered heart rate (HR) and mean arterial pressure (MAP); the decrease in blood pressure recovered faster as compared to the HR. The effects of endomorphin 2 were qualitatively similar. Naloxone (2 mg/kg, i.v.) completely antagonized the bradycardia and hypotension caused by endomorphin 1. Pretreatment of the rats with atropine methylnitrate, atropine sulfate (2 mg/kg, i.v.) or bilateral vagotomy nearly abolished the bradycardia and attenuated the hypotensive effect of endomorphin 1. Our studies suggest that the bradycardia effect following systemic administration of the new opioid peptide may be explained by activation of vagal afferents and the hypotensive effect may be secondary to a reduction of cardiac output and/or a direct vasodilation.

Human immunodeficiency virus type 1 (HIV-1) persists in certain CNS cell populations, despite peripheral control of the infection with modern antiretroviral therapy. Infected and/or activated cells release viral proteins, such as trans-activator of transcription (Tat) and various pro-inflammatory factors such as CCL5, creating a positive loop of neuro-inflammation. This serves as the basis for the resulting sublethal and lethal neuropathology that manifests as a spectrum of HIV-mediated CNS impairments, known as HIV-associated neurocognitive disorders (HAND). Opiates, which exist as an interlinked epidemic with HIV-1 infections, exacerbate these neurological effects through direct and indirect mechanisms that disrupt both glial and neuronal function. We hypothesize this is due to converging actions on the CCL5-CCR5 signaling axis by HIV-1 Tat and morphine co-exposure, primarily mediated at the level of the glia, whose consequent activation leads to neuronal damage. We performed repeated measure studies on mixed glia and neuron co-cultures obtained from C57Bl/6J and/or CCR5 knockout mice, treated with Tat and/or morphine for 72 hours. As established in prior studies, morphine worsened Tat-induced neurotoxicity in wild-type co-cultures; substitution of CCR5-null glia eliminated the interactive effects of Tat and morphine, but substitution of CCR5-null neurons did not. Overall, these results suggest that glial CCR5, but not neuronal CCR5, is a convergence point for the interactive effects of Tat and morphine that result in neuron loss. Additional experiments involving treatments with naloxone, a MOR antagonist, or the CCR5 antagonist maraviroc, confirmed each receptor’s role in mediating Tat + morphine toxicity. Quite surprisingly, in co-cultures of wild-type neurons and CCR5-null glia, morphine entirely protected neurons from the neurotoxic effects of Tat. We hypothesize that this effect may reflect an imbalance of neurotrophic factors, particularly BDNF and its neurotoxic precursor proBDNF, whose levels are altered in HIV+ and illicit drug-using patients and may contribute to changes in neuronal signaling and survival exhibited in HAND. Related behavioral tests of anxiety, motor and cognitive function – three areas of neurologic decline seen in HAND – were performed in inducible Tat-transgenic mice that were treated with maraviroc via oral gavage. Tat-mediated impairment was observed in the Barnes Maze, a measure of spatial memory, and was ameliorated by maraviroc. Finally, we assessed the role of CCR5 in mediating Tat and/or morphine effects on psychomotor sensitization and dendritic morphology. With both in vitro and in vivo studies, our findings support the hypothesis that CCR5 plays a central role in driving HIV-1 Tat and/or morphine-mediated neuronal damage.

Addiction to opiates is a complex public health issue affecting thousands of Canadians. Methadone Maintenance Treatment (MMT) is considered the gold standard in Canada, and the world, for treating opiate dependence. In the past, Canadian research into opiate addiction and the effectiveness of MMT has mostly focused on larger cities: Toronto, Montreal, and Vancouver. This community based research study employed a mixed method approach to gain understanding of the experiences and satisfaction with MMT and other health services available to opiate users in Belleville, Ontario (population 48,000). Surveys (N = 53), focus groups, participant-observation methods and key informant interviews were used to gather data. The results provide an overall picture of the quality of life for opiate users and MMT clients, the quality of care clients receive, and the perceptions of community members regarding MMT. Challenges related to smaller locales are identified along with recommendations for improving MMT health services. / UOIT

The underlying mechanism of morphine tolerance remains unclear. EphB2 regulates synaptic efficiency with respect to learning and memory. Previously, we demonstrated that loss of EphB2 significantly accelerates the rate of morphine tolerance and alters behavioural responses to morphine following tolerance. However, EphB2 null mice exhibit no significant alteration in their metabolism of morphine compared to littermate controls, or altered mu opioid receptor expression levels within the spinal cord or brain compared to littermate controls. Therefore, we investigated whether loss of EphB2 alters learned responsiveness to morphine through modification of hippocampal function. Interestingly, results indicate that electrolytic lesions of the dorsal hippocampus of wild-type mice display similar behavioural responses seen in EphB2 null mice compared to sham operated controls. These findings suggest that loss of EphB2 function within the hippocampus is a critical feature in mediating morphine-dependent tolerance, and suggests a novel role for EphB2 receptor signaling in opiate-dependent learning.

The underlying mechanism of morphine tolerance remains unclear. EphB2 regulates synaptic efficiency with respect to learning and memory. Previously, we demonstrated that loss of EphB2 significantly accelerates the rate of morphine tolerance and alters behavioural responses to morphine following tolerance. However, EphB2 null mice exhibit no significant alteration in their metabolism of morphine compared to littermate controls, or altered mu opioid receptor expression levels within the spinal cord or brain compared to littermate controls. Therefore, we investigated whether loss of EphB2 alters learned responsiveness to morphine through modification of hippocampal function. Interestingly, results indicate that electrolytic lesions of the dorsal hippocampus of wild-type mice display similar behavioural responses seen in EphB2 null mice compared to sham operated controls. These findings suggest that loss of EphB2 function within the hippocampus is a critical feature in mediating morphine-dependent tolerance, and suggests a novel role for EphB2 receptor signaling in opiate-dependent learning.