The presence of μ-, δ- and κ-binding sites in homogenates of guinea-pig brain was demonstrated by the use of selective labelling techniques. In saturation experiments, the tritiated ligands [^3H]-[D-Ala^2, MePhe^4, Gly-ol^5]enkephalin, [^3H]-dihydromorphine, [^3H]-morphine and [^3H]-dihydronormorphine labelled only the μ-binding site. The δ-binding site could be labelled selectively with [^3H]-[D-Pen^2, D-Pen^5]enkephalin. However, the less selective δ-ligand, [³H]-[D-Ala², D-Leu⁵] enkephalin, could only be used when its μ-binding was blocked with the unlabelled μ-ligand [D-Ala², MePhe⁴, Gly-ol⁵]enkephalin. Selective labelling of the κ-binding site was more of a problem since the non-selective ligands [^3H]-etorphine, [^3H]-(±)-ethylketazocine and [³H]-(-)-bremazocine bind to the μ-, δ- and κ-sites. Therefore, the κ-binding site could only be labelled selectively when the binding of the tritiated ligands to the μ- and δ-sites was prevented by addition of the unlabelled μ-ligand [D-Ala^2, MePhe^4, Gly-ol^5]enkephalin and the unlabelled δ-ligand [D-Ala², D-Leu⁵]enkephalin. By analysis of the saturation curves obtained using these selective labelling techniques, the proportion of binding sites in homogenates of guinea-pig brain at 25°C was 24% μ-sites; 32% δ-sites and 44% κ-sites. The selective labelling techniques were also used to label the μ, δ- and κ-sites in displacement assays. The compounds with the highest degree of preference for each binding site were: for the μ-site, [D-Ala^2, MePhe^4, Gly-ol^5]enkephalin and Tyr-Pro-MePhe-D-Pro-NH_2; for the δ-site, [D-Pen², L-Pen⁵]enkephalin, [D-Pen², D-Pen⁵]enkephalin and ICI 174864 and for the κ-site, U-50,488H and U-69,593. As far as antagonists were concerned, naloxone displayed the highest preference for the μ-binding site and Mr 2266 had a preference for the κ-binding site but neither compound was highly selective unlike the δ-antagonist ICI 174864. The effect of pre-incubation with β-funaltrexamine on opioid binding was investigated in homogenates of guinea-pig brain and myenteric plexus-longitudinal muscle.

Indiana University-Purdue University Indianapolis (IUPUI) / The opioid crisis has resulted in an unprecedented number of neonates born with prenatal opioid exposure; however, the long-term effects of opioid exposure on offspring behavior and neurodevelopment remain relatively unknown. I developed a translational mouse model of prenatal methadone exposure (PME) that resembles the typical pattern of opioid use by pregnant women who first use oxycodone then switch to methadone maintenance pharmacotherapy, and subsequently become pregnant while maintained on methadone. PME produced substantial impairments in offspring growth, sensorimotor milestone acquisition, and activity in an open field. Furthermore, these behavioral alterations were associated with significant disruptions in the primary motor cortex (M1). Notably, layer 5 pyramidal neurons of the M1 displayed significantly increased voltage sag which is primarily mediated by HCN1 channels. Interestingly, the α2-adrenergic receptor, a known modulator of HCN1 channels, displayed significantly increased expression in the M1 of PME animals. The locomotor activity in an open field was significantly reduced following in vivo pharmacological activation of the α2-adrenergic receptor with clonidine in PME offspring suggesting this may be therapeutic target for the hyperactivity associated with prenatal exposure to opioids. Previous work has also described an association between prenatal opioid exposure and alterations in opioid reward-related behavior; however, the effect of PME on alcohol reward remains undetermined. Given the widespread accessibility and usage, alcohol represents the most likely addictive substance the growing population of opioid exposed neonates will encounter as they age. I discovered that PME disrupts conditioned preference for alcohol, enhances the locomotor stimulating effects of alcohol, and increases alcohol consumption in a sex-dependent manner. This alcohol-reward phenotype in PME offspring was associated with altered excitatory neurotransmission and disrupted cannabinoid-mediated long-term depression (CB-LTD) in the dorsolateral striatum, an important substrate involved in compulsive drug use. Further work is required to determine the specific inputs at which CB-LTD is disrupted and if restoring this form of plasticity in PME animals prevents the enhanced alcohol addiction phenotype. / 2023-03-02

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 6 uppsatser.

Thesis (Ph. D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Medicinal Chemistry. Title from title-page of electronic thesis. Bibliography: leaves 126-138.

Thesis (M.A.)--Boston University / Cocaine use among opioid dependent persons is common, with an estimated 40 to 70% of those seeking treatment for opioid dependence, also using cocaine (Sullivan et al., 2011 ). The effects of cocaine use on treatment outcomes for those seeking medication assisted treatment (MAT) for opioid dependence are not well understood. Buprenorphine, prescribed under the brand name Suboxone, has recently emerged as a convenient, effective method of MAT. The Facilitated Access to Substance Abuse Treatment with Prevention And Treatment of HIV (FAST PATH) program at Boston Medical Center, is a research study to provide substance abuse treatment along with primary care and HIV risk-reduction counseling to those afflicted with these epidemics. The objective of this study was to determine the association of cocaine use with treatment retention and opioid abstinence at six months for patients receiving buprenorphine in the FAST PATH program. A prospective cohort study was conducted on 116 patients enrolled in the FAST PATH program through 02/01/2012. Assessments were conducted at baseline and six months to evaluate the association between baseline cocaine use and treatment retention as well as opioid abstinence at six months. Baseline cocaine use was measured by either any urine toxicology screen positive for cocaine prior to study enrollment or 30 day self-reported cocaine use on the initial assessment. Of the 116 participants, 39% were positive for cocaine use at baseline and 52% were HIV positive. Baseline cocaine use had no effect significant on treatment retention or opioid abstinence at six months. Among all the participant characteristics measured, there were no significant differences between the cocaine positive (n=45) and cocaine negative (n=71) groups. In adjusted analysis, age was the only covariate which was significant at predicting the odds of treatment retention or opioid abstinence with a 1.11 (p-value = 0.0003) and 1.08 (p-value = 0.02) greater odds of each, respectively. Although cocaine use did not affect the dependent variables, integrated substance abuse and primary care clinics utilizing buprenorphine are a rich area of future research. Specifically, subsequent studies should determine how varied groups of opioid dependent persons perform within this framework, and the underlying characteristics moderating their outcomes.

No description available.

No description available.

With an increasing prevalence of osteoarthritis, total knee (TKA) and hip (THA) arthroplasty are the second-and third-most common surgeries in Canada. Although these procedures improve pain and function for a majority of patients, some patients report persistent postoperative pain. Opioids are conventionally used for these patients even though they are associated with addiction, falls, overdose, and death. Recently, many strategies have been proposed to decrease reliance on opioids after TKA and THA, including opioid-free and opioid-reduced multimodal protocols for pain management. Our findings demonstrate that Canadian patients’ receptivity to opioid-free or reduced postoperative protocols is associated with their perception of the efficacy and safety of opioids compared to non-opioid alternatives, and current opioid use. More patients are open to opioid-reduced postoperative care as they perceive that pain will be intolerable without opioids. This overlaps with many Canadian surgeons’ perception that opioids cannot be completely eliminated from postoperative pain management regimens and that patients expect an intolerable level of pain after surgery, warranting opioid use. This highlights a need for enhanced patient education on the safety and efficacy of opioids and alternatives, while managing patients’ expectations of postoperative pain control. Most Canadian and Dutch surgeons reported that they prescribe opioids to nearly all of their patients postoperatively. However, our cross-sectional study indicates that 40% of Canadian patients would be open to receiving no opioids postoperatively. In contrast, Japanese surgeons believed that opioids are unnecessary for managing postoperative pain. Variations observed among orthopaedic surgeons in Canada, the Netherlands, and Japan can be attributed to differences at the surgeon-level (individual practices and beliefs), patient-level (patient characteristics and preferences), and system-level (regulatory frameworks and healthcare systems). Further research is required on surgeon-centered approaches to mitigating opioid use, focusing on education and guidelines/policies for opioid prescribing. / Thesis / Master of Science (MSc) / Opioid analgesics are routinely prescribed to manage pain after total knee and hip replacement surgery. However, opioids are not typically more effective than alternatives and are associated with addiction, overdose, and death. This thesis aims to understand the perceptions of patients and orthopaedic surgeons on opioid use after total knee and hip replacement surgery. The findings demonstrate that more patients are open to receiving opioid-reduced surgery compared to opioid-free surgery, with receptivity being associated with patients’ perceptions of opioid efficacy and safety and current opioid use, highlighting a need for improved patient education. Additionally, orthopaedic surgeons identified challenges and facilitators to postoperative opioid reduction in six key areas: opioid prescribing practices, patient factors, collaborative care, policies/guidelines, surgeon education and training, and personal perceptions/beliefs. Compared to Canadian and Dutch surgeons, Japanese surgeons heavily relied on non-opioid medications as they believed that opioids are unnecessary for managing postoperative pain.