The misuse of prescription opiates is on the rise with combination therapies (e.g. acetaminophen or NSAIDs) resulting in severe liver and kidney damage. In recent years, cannabinoid receptors have been identified as potential modulators of pain and rewarding behaviors associated with cocaine, nicotine and ethanol in preclinical models. Furthermore, activation of cannabinoid 2 (CB2) receptors on immune cells through the inhibition of monoacylglycerol lipase (MAGL), results in increased 2-arachidonylglycerol (2AG) production and analgesia in animal models. Yet, few studies have identified whether mu opioid and CB2 receptor agonists act synergistically to inhibit chronic pain while reducing unwanted side effects including reward liability, or if it could ameliorate the excruciating pain that is poorly managed with by opiates in bone cancer patients. We determined if analgesic synergy exists between the mu-opioid agonist morphine and the selective CB2 agonist, JWH015, or the inhibitor of MAGL, MJN110, in rodent models of acute and chronic inflammatory, post-operative, neuropathic, and cancer-induced bone pain (CIBP) using isobolographic analysis. We also investigated if the MOR-CB2 agonist combination decreased morphine-induced conditioned place preference (CPP) and slowing of gastrointestinal transit. Next, we examined whether JWH015 or the inhibition of MAGL decreased the release of pro-inflammatory mediators by activating nuclear factor kappa enhancer of activated B cells (NFkB), as dysregulation of NFkB is observed in various cancers. Here we show that MOR + CB2 agonism results in a significant synergistic inhibition of preclinical pain while significantly reducing opioid-induced unwanted side effects. The opioid sparing effect of CB2 receptor agonism strongly supports the advancement of a MOR-CB2 agonist combinatorial pain therapy for clinical trials.

Master of Science / Department of Clinical Sciences / Warren L. Beard / Pharmacokinetics of Intramuscular Morphine in the Horse Elizabeth Devine, DVM; Butch KuKanich, DVM, PhD, DACVCP; Warren Beard, DVM, MS, DACVS Objective - To determine the pharmacokinetics of morphine after intramuscular administration in a clinical population of horses Design – Prospective, clinical study Animals – Pilot study included 2 normal horses and the clinical study included 75 horses Procedures – Morphine was administered at 0.1mg/kg, IM and 2-3 blood samples were obtained from each horse at various times from 0-9 hours after administration. Plasma morphine concentrations were measured using liquid chromatography and mass spectrometry. Results – Data was analyzed using a naïve pooled pharmacokinetic model. The half-life for the elimination phase was approximately 1.5 hours, the volume of distribution (per bioavailability) was approximately 4.5 L/kg and the clearance (per bioavailability) was approximately 35 mL/kg/min. The peak plasma concentration was 21.6 ng/mL and occurred approximately 4 minutes after administration. Plasma concentrations of morphine were below the limit of quantification by 7 hours in 74 horses. Conclusions and Clinical Relevance – The relatively short half-life of morphine indicates the need for frequent dosing to maintain targeted plasma concentrations. Adverse effects were uncommon in this study and morphine was well tolerated at a dose of 0.1 mg/kg, IM. Morphine may be a useful adjunctive therapy in painful horses, but the variable plasma concentrations suggest the dose and dosing interval may need to be adjusted to the individual patient’s response.

by Hing Kee Wong. / Title also in Chinese. / Thesis (M.Phil.)--Chinese University of Hong Kong. / Bibliography: leaves 67-74.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Many patients present with upper abdominal pain and receive some type of pain relieving therapy prior to gallbladder imaging. The physiologic effect of morphine and other analgesics on gallbladder function has been well‐studied. What hasn’t been studied as much are the implications on clinical practice and the decision about whether morphine is the best option to use in suspected chronic gallbladder disease. This case study serves to illustrate the influence of morphine in a patient who underwent both inpatient and outpatient hepatobiliary scintigraphy with dramatically different results. This case study perfectly shows the considerations that must be taken when using morphine because it eliminates many confounding variables; the only difference in the patient at the time of initial and subsequent presentation was the presence of morphine.

For thesis abstract select View Thesis Title, Contents and Abstract

For thesis abstract select View Thesis Title, Contents and Abstract

Graduation date: 1999

A crucial question in drug addiction research concerns whether the varying reports of dopamine-independent and dopamine-dependent motivation can be integrated. According to one theory, the prior drug history of a subject — that is to say, whether they have received minimal or chronic drug exposure — determines whether opiate motivation is dependent upon the brainstem tegmental pedunculopontine nucleus (TPP) or dopamine neurotransmission. The biological analogue of this change is thought to be a switch in the signalling properties (from hyperpolarizing to depolarizing) of ventral tegmental area (VTA) gamma-aminobutyric acid subtype-A (GABAA) receptors. In this thesis, I demonstrate that the mechanisms underlying opiate motivation can be selected artificially by manipulating the signalling properties of VTA GABAA receptors, irrespective of the past drug history of the subject. Furthermore, I suggest that these same VTA GABAA receptors also play a similar role in controlling ethanol motivation. Indeed, the mechanisms underlying ethanol motivation can be doubly dissociated in a manner similar to that observed with opiates. However, whereas opiate motivation is TPP-dependent in the drug-naive state, I found that ethanol motivation was dependent on dopamine neurotransmission (via the D2 receptor) in drug-naive animals. Conversely, ethanol motivation was TPP-dependent in ethanol-deprived mice (as opposed to opiate motivation being dopamine-dependent in opiate-deprived animals). These effects are consistent with a VTA GABAA receptor switching mechanism identical to the one seen in the case of opiate motivation.

Chronic pain in the aged is a widespread phenomenon, and morphine is the most commonly used narcotic analgesic for treatment. Despite that fact, there are relatively few published studies examining the impact of advanced age on morphine analgesia. We hypothesized that aged rats would be less sensitive to morphine than adults, and that aged animals would have reduced mu-opioid receptor (MOR) binding and expression in the ventrolateral periaqueductal gray, a brain region responsible for morphine analgesia. Using a model of persistent inflammatory pain, we found that morphine was significantly less effective in aged males compared to adult males, and that aged males and females experience a reduction in MOR binding and expression compared to adults. These results suggest that there are clear age differences in morphine efficacy, and that reductions in MOR binding and expression in the periaqueductal gray could underlie those differences.

Social factors influence drug abuse in adolescents; this is partially attributed to peer pressure in humans. Similarly, using rodent models, some research suggests that social housing condition can influence rodents' drug taking behavior. Despite this, few studies have examined the role that intoxicated peers have on drug-naive cage-mates. This dissertation examined how social environment affects opioid sensitivity and hormone production. This was accomplished by comparing the opioid sensitivity of mice housed in mixed cages (some animals received opioids and some were drug-naive) to cages where all the mice were treated with the same drug (all saline or all morphine). These studies identified an adolescent-specific vulnerability to social environment-induced alteration of morphine sensitivity. Interaction with drug-intoxicated cage-mates enhanced locomotor sensitivity in previously drug-naive males and altered their production of testosterone. Conversely, interaction of morphine experienced mice with drug-naive cage-mates afforded protection from the rewarding properties of morphine. In other words, morphine-treated mice housed with drug-naive cage-mates demonstrated attenuated reward compared to morphine-treated mice housed with other morphine-treated mice. In addition, part of the neurobiological basis of the social-environment effect was identified. Antagonism of V1b receptors decreased morphine reward in morphine-treated mice housed only with other morphine-treated mice. These results suggest a role of vasopressin in the peer influence on drug sensitivity observed in adolescents. This body of work further elucidates the role of peer influence on opioid sensitivity. Future studies should further reveal the role of healthy peer relationships and should aid in combating drug abuse in this at-risk demographic.