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Articles 1 - 17 of 17
Full-Text Articles in Medicine and Health Sciences
Investigating Cannabinoid Type-1 Receptor (Cb1r) Positive Allosteric Modulators (Pams) In Mouse Models Of Overt Cannabimimetic Activity, Subjective Drug Effects, And Neuropathic Pain, Jayden Elmer
Theses and Dissertations
Chronic pain affects between 20 and 30 percent of the adult population in western countries and represents a wide array of specific etiologies (Berge, 2011). Neuropathic pain secondary to traumatic nerve injury, chemotherapeutic toxicity, or diseases (e.g., diabetes mellitus) is often refractory to conventional analgesics, with patients receiving less than 50% pain relief compared to placebo (Finnerup et al. 2010). The endocannabinoid system has shown potential as a therapeutic target for neuropathic pain wherein CB1 agonism via administration of exogenous agonists or pharmacological blockade of endocannabinoid catabolic enzymes exhibits efficacy in reversing allodynia in the chronic constriction injury (CCI) model …
In Vivo Effects Of The Cb1 Allosteric Modulator Ldk1258, A Structural Analog Of Org-27569, Mohammed A. Mustafa
In Vivo Effects Of The Cb1 Allosteric Modulator Ldk1258, A Structural Analog Of Org-27569, Mohammed A. Mustafa
Theses and Dissertations
CB1 receptor allosteric modulators are an area of growing interest for their potential novel therapeutic actions. In the present study, we examined LDK1258 in a series of pharmacological in vivo tests sensitive to CB1 receptor stimulation. In the tetrad assay, LDK1258 produced significant decreases in locomotor activity and body temperature measures but did not produce either antinociception as measured in the tail-withdrawal assay or catalepsy as assessed in the bar test. These same effects were observed in both CB1 (-/-) and (+/+) mice. Moreover, LDK1258 failed to shift the dose-response curves of two orthosteric CB1 receptor agonists in the triad …
Role Of Epigenome And Microbiome In Cannabinoid And Aryl Hydrocarbon Receptor-Mediated Regulation Of Inflammatory And Autoimmune Diseases, Zinah Zamil Al-Ghezi
Role Of Epigenome And Microbiome In Cannabinoid And Aryl Hydrocarbon Receptor-Mediated Regulation Of Inflammatory And Autoimmune Diseases, Zinah Zamil Al-Ghezi
Theses and Dissertations
Inflammation is considered to be the underlying cause of a majority of clinical disorders. Thus, studies aimed at understanding the signaling pathways that trigger inflammation could have significant translational impact. In the current study, we investigated the effect of activation of cannabinoid (CB) and Aryl hydrocarbon hydroxylase (AhR) receptors on the inflammatory response. To that end, we used cannabinoids such as Δ (9)-Tetrahydrocannabinol (THC) and cannabidiol (CBD), and a well-established AhR agonist namely 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD). These were tested against two inflammatory disease models: 1) Experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis (MS), and 2) Exposure to …
Cannabinoid-Mediated Epigenetic Regulation Of Immune Functions, Jessica Margaret Sido
Cannabinoid-Mediated Epigenetic Regulation Of Immune Functions, Jessica Margaret Sido
Theses and Dissertations
The cannabinoid system consisting of exogenous and endogenous ligands as well as dedicated receptors has been proposed to play a regulatory role in immune functions. The exogenous cannabinoid Δ9-tetrahydrocannabinol (THC), one of the most widely studied marijuana derivatives, has been associated with multiple anti-inflammatory properties over the years. The majority of THC research has centered on the shift from Th1 to Th2 responses however, the complexity of inflammation has since increased. Recent studies have revealed that epigenome, Th cell subsets, and immunoregulatory cell induction, are all known to impact inflammation. In the current research, we have attempted to look holistically …
Combined Antiproliferative Effects Of The Aminoalkylindole Win55,212-2 And Radiation In Breast Cancer Cells, Sean Emery
Combined Antiproliferative Effects Of The Aminoalkylindole Win55,212-2 And Radiation In Breast Cancer Cells, Sean Emery
Theses and Dissertations
The potential antitumor activity of mixed CB1/CB2 cannabinoid receptor agonists, such as the aminoalkylindole WIN55,212-2 (WIN2), has been extensively studied, but little information is available as to their potential interaction with conventional cancer therapies, such as ionizing radiation (IR). In the present work, we investigated the effects of WIN2 on the antiproliferative effects of radiation in human (MCF-7 and MDA-MB-231) and murine (4T1) breast cancer cells, as well as an immortalized human breast epithelial cell line (MCF-10A). WIN2 or radiation alone inhibited breast tumor growth, while the combination of WIN2 and radiation was more effective than either agent alone in …
Differential Effects Of Endocannabinoid Catabolic Inhibitors On Opioid Withdrawal In Mice, Thomas Gamage
Differential Effects Of Endocannabinoid Catabolic Inhibitors On Opioid Withdrawal In Mice, Thomas Gamage
Theses and Dissertations
The effects of cannabinoids in reducing somatic signs of opioid withdrawal have been known for some time. In morphine dependent rodents, opioid withdrawal following precipitation with the mu opioid antagonist naloxone elicits robust withdrawal behaviors including jumps, paw flutters, head shakes, diarrhea and weight loss. Delta-9-tetrahydrocannabinol has been shown to reduce this opioid withdrawal in mice via activation of the cannabinoid type-1 (CB1) receptor and recently it has been shown that inhibition of the catabolic enzymes for endocannabinoids also reduce somatic signs of opioid withdrawal. Specifically, inhibition the enzyme fatty acid amide hydrolase (FAAH), the catabolic enzyme for the endocannabinoid …
Effect Of Cannabinoids On Pain-Stimulated And Pain-Depressed Behavior In Rats, Andrew Kwilasz
Effect Of Cannabinoids On Pain-Stimulated And Pain-Depressed Behavior In Rats, Andrew Kwilasz
Theses and Dissertations
Cannabinoids produce antinociception in many preclinical models of acute and chronic pain. In contrast, cannabinoids produce inconsistent analgesia in humans, showing little or no efficacy in treating acute pain, with modest efficacy in treating chronic inflammatory pain. This discrepancy may reflect an overreliance on preclinical assays of pain-stimulated behaviors, defined as behaviors that increase in rate or intensity following delivery of a noxious stimulus. In these assays, antinociception is indicated by a reduction in pain-stimulated behaviors, and antinociception is produced either by a reduction in sensory sensitivity to the noxious stimulus (i.e. true analgesia) or by false positive motor impairment. …
Thc-Mediated Induction Of Δfosb And Its Modulation Of Cb1r Signaling And Adaptation, Lazenka Matthew
Thc-Mediated Induction Of Δfosb And Its Modulation Of Cb1r Signaling And Adaptation, Lazenka Matthew
Theses and Dissertations
The main psychoactive and therapeutic effects of Δ9-tetrahydrocannabinol (THC) are mediated through cannabinoid type 1 receptors (CB1Rs). The therapeutic uses of THC are mitigated by the development of tolerance to these therapeutic effects, whereas tolerance does not readily develop to some of the side-effects of THC, like motor impairment and reward. The development of tolerance occurs through adaptations at CB1Rs, which include desensitization (G-protein uncoupling) and downregulation (receptor degradation). Brain region-dependent differences in THC-mediated adaptations are proposed to explain the differences in tolerance to various THC-mediated effects. These studies focused on whether ΔFosB, a stable transcription factor, could regulate CB1R …
Characterization And Development Of A Stroke-Induced Model Of Acquired Epilepsy In Organotypic Hippocampal Slice Cultures: Role Of The Cannabinoid Cb1 Receptors In Modulation Of Neuronal Excitation And Inhibition, Julie Ziobro
Theses and Dissertations
Stroke is the most common cause of acquired epilepsy in persons 35 and older. The massive increase in extracellular glutamate during stroke causes a cascade of intracellular events that can lead to cell death or the molecular changes that initiate the development of epilepsy. In addition, many studies point to a modulatory role of the endocannabinoid system in controlling seizures. Animal models of stroke induced acquired epilepsy have been difficult to develop. Therefore, this dissertation was initiated to develop an organotypic hippocampal slice culture model of acquired epilepsy and examine the changes in distribution and function of the endogenous CB1 …
Differential Roles Of The Two Major Endocannabinoid Hydrolyzing Enzymes In Cannabinoid Receptor Tolerance And Somatic Withdrawal, Joel Schlosburg
Differential Roles Of The Two Major Endocannabinoid Hydrolyzing Enzymes In Cannabinoid Receptor Tolerance And Somatic Withdrawal, Joel Schlosburg
Theses and Dissertations
While there is currently active debate over possible therapeutic applications of marijuana and cannabis-based compounds, consistently their primary drawbacks have been the psychoactive properties, dependence, and abuse potential. Prolonged administration of ∆9-tetrahydrocannabinol (THC), the primary psychoactive constituent in marijuana, demonstrates both tolerance and physical withdrawal in both preclinical and clinical studies. Repeated THC administration also produces CB1 receptor adaptations in the form of reduced activation of receptors, along with a downregulation of membrane surface receptors, in many brain regions involved in THC-associated behaviors. The increased need for drug to maintain therapeutic effects, and a withdrawal syndrome following discontinuation of use, …
Effects Of Cannabinoid Receptor Interacting Protein (Crip1a) On Cannabinoid Receptor (Cb1) Function, Tricia Smith
Effects Of Cannabinoid Receptor Interacting Protein (Crip1a) On Cannabinoid Receptor (Cb1) Function, Tricia Smith
Theses and Dissertations
EFFECTS OF CANNABINOID RECEPTOR INTERACTING PROTEIN (CRIP1a) ON CANNABINOID (CB1) RECEPTOR FUNCTION. By Tricia Hardt Smith, B.S., M.S. A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University Virginia Commonwealth University, 2009. Major Director: Dana E. Selley, Ph.D., Department of Pharmacology and Toxicology This dissertation examines modulation of cannabinoid CB1 receptor function by Cannabinoid Receptor Interacting Protein (CRIP1a), a novel protein that binds the C-terminus of CB1 receptors. In Human embryonic kidney cells expressing human CB1 receptors (hCB1-HEK) and hCB1-HEK cells stably co-expressing CRIP1a (hCB1-HEK-CRIP1a), quantitative immunoblotting revealed a CRIP1a/CB1 …
The Effect Of Chronic Constriction Injury On Cellular Systems Within Nociceptive Pathways In The Mouse, Michelle Hoot
The Effect Of Chronic Constriction Injury On Cellular Systems Within Nociceptive Pathways In The Mouse, Michelle Hoot
Theses and Dissertations
Chronic neuropathic pain is often difficult to treat due to its resistance to therapeutic intervention. This is due in part to the poor understanding of the physiological mechanisms involved in the establishment and maintenance of neuropathic pain states. The neuropathic pain model, chronic constriction injury of the sciatic nerve, produced robust pain hypersensitivity in our mice. It also induced significant changes in the mitogen activated protein kinase family, and the cannabinoid and µ-opioid systems in three different brain areas involved in the modulation or regulation of pain states. CCI induced a 2.5 fold increase in mRNA of the kinase Raf-1 …
A Comparision Of Delta-9-Tetrahydrocannabinol Dependence In C57bl/6j Mice And Fatty Acid Amide Hydrolase Knock Out Mice, Brittany Leigh Alice Carlson
A Comparision Of Delta-9-Tetrahydrocannabinol Dependence In C57bl/6j Mice And Fatty Acid Amide Hydrolase Knock Out Mice, Brittany Leigh Alice Carlson
Theses and Dissertations
The idea that humans and laboratory animals can become physically dependent on marijuana or its primary psychoactive constituent, delta-9-tetrahydrocannabinol (THC), is gaining acceptance. However, there are no currently approved pharmacotherapies to treat cannabinoid withdrawal. The objective of this thesis was to evaluate whether elevating endogenous anandamide levels using mice lacking fatty acid amide hydrolase (FAAH), the enzyme responsible for anandamide metabolism, would ameliorate THC dependence. Mice were treated subchronically with a low or high THC dosing regimen and challenged with the CB1 receptor antagonist, rimonabant, to precipitate withdrawal. Following subchronic THC treatment, rimonabant precipitated a significant increase in paw flutters …
Functional Redistribution Of Hippocampal Cannabinoid Cb1 Receptors In The Rat Pilocarpine Model Of Acquired Epilepsy, Katherine Winslow Falenski
Functional Redistribution Of Hippocampal Cannabinoid Cb1 Receptors In The Rat Pilocarpine Model Of Acquired Epilepsy, Katherine Winslow Falenski
Theses and Dissertations
Cannabinoids, such as the marijuana derivative Δ9-THC, are known to have CBl receptor-mediated anticonvulsant effects in several animal models of seizures and epilepsy, including the rat pilocarpine model of acquired epilepsy. However, the distribution of CBl receptor expression and function in brains of epileptic rats has not been characterized. Therefore, this dissertation was initiated to evaluate the effect of epileptogenesis on the distribution and function of the endogenous CBI receptor system in the rat pilocarpine model, a well-established model of acquired temporal lobe epilepsy. Using immunohistochemistry, we demonstrated that chronically epileptic rats exhibit a unique, long-term, and specific redistribution of …
The Influence Of Sustained Cb1 Blockade During Adolescence On Breakpoints In A Progressive-Ratio Paradigm, Mayo Jerry Wright Jr.
The Influence Of Sustained Cb1 Blockade During Adolescence On Breakpoints In A Progressive-Ratio Paradigm, Mayo Jerry Wright Jr.
Theses and Dissertations
The developmental psychopharmacology of cannabinoids is poorly understood and little is known about the developmental consequences of repeated exposure to cannabinoid antagonists. In these experiments, male Long-Evans rats were treated with SR141716A, a cannabinoid antagonist, throughout adolescence and allowed unrestricted access to food. Control groups were treated with vehicle during the same developmental period and allowed either unrestricted access to food or were pair-fed with a member of the SR-treated group. Motivation to work for food was measured in progressive-ratio sessions at varying levels of food deprivation. For rats that consumed fewer calories throughout adolescence, whether because of pharmacological intervention …
Relationship Between Cb1 And S1p Receptors In The Central Nervous System, Lauren Michele Collier
Relationship Between Cb1 And S1p Receptors In The Central Nervous System, Lauren Michele Collier
Theses and Dissertations
There is significant sequence homology and anatomical co-distribution between cannabinoid (CB1) and sphingosine-1-phosphate (S1P) receptors in the CNS, but potential functional relationships between these lysolipid receptors have not been examined. Therefore, to investigate possible relationships between these two systems at the level of G-protein activation, agonist-stimulated [35S]GTPγS binding and autoradiography were conducted. Autoradiographic studies were first performed to localize receptor-mediated G-protein activation in mouse brain. Coronal brain slices were processed for stimulation of [35S]GTPγS binding using the synthetic cannabinoid agonist WIN 55,212-2 (WIN) or SIP. High levels of WIN- and S1P-stimulated [35S]GTPγS binding were observed in the caudate putamen, hippocampus, …
The Study Of The Effect Of Drugs Of Abuse On Protein Kinase A Activity In Mouse Brain And Spinal Cord, George D. Dalton
The Study Of The Effect Of Drugs Of Abuse On Protein Kinase A Activity In Mouse Brain And Spinal Cord, George D. Dalton
Theses and Dissertations
Morphine and Δ9-THC are drugs that produce analgesia and rewarding effects. However, chronic treatment with morphine and Δ9-THC produces problematic side-effects including tolerance and physical dependence. The cellular mechanisms underlying opioid and cannabinoid antinociceptive tolerance have been studied for years. Research has demonstrated that the expression of morphine and Δ9-THC antinociceptive tolerance may be mediated through intracellular signaling pathways, such as the adenylyl cyclase /Protein Kinase A (PKA) cascade. The present study investigated the role of PKA in the expression of morphine and Δ9-THC antinociceptive tolerance. Male Swiss Webster mice were treated chronically with morphine or Δ9-THC and the warm-water …