Persistent Link:
http://hdl.handle.net/10150/280554
Title:
Pain-modulating effects of peripheral (CB2) cannabinoid receptors
Author:
Ibrahim, Mohab Mohamed
Issue Date:
2004
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Cannabinoid receptor agonists diminish responses to painful stimuli. Extensive evidence implicates the CB1, receptor in the production of antinociception, inflammatory hyperalgesia, and peripheral nerve injury-induced sensory hypersensitivity. In previous work included in my masters thesis, our laboratory has demonstrated the capacity of CB2 receptors located outside the central nervous system (CNS) to inhibit acute nociception and inflammatory hyperalgesia. In this thesis, I use AM1241, a CB2 receptor-selective agonist to test the hypothesis that CB2 receptor activation reverses the tactile and thermal hypersensitivity characteristic of neuropathic pain in L5/L6 spinal nerve ligation model. The CB2 receptor-mediated nature of these effects was demonstrated using receptor-selective antagonists, as well as mice deficient in the genes coding for CB1 or CB2 receptors. Experiments using site-specific injections suggest AM1241 acts peripherally at the site of nerve injury and the site of application of the sensory stimulus. The peripheral nature of the effects of AM1241 is consistent with the peripheral distribution of CB 2 receptors. Given the peripheral actions of AM1241, I hypothesized and demonstrated that topical application of AM1241 modulates pain responses. Additionally, I began to examine the mechanisms by which CB2 receptor activation modulates pain responses. The effects of AM1241 were reversed by the opioid receptor antagonist, naloxone and by a sequestering antiserum to beta-endorphin. In addition, the effects of AM1241 were not observed in beta-opioid receptor knockout mice. These results suggest that the endogenous opioid peptide, mu-endorphin plays an essential role in CB2 receptor mediated pain inhibition. Further, AM1241 stimulated release of beta-endorphin from rat skin tissue and cultured human keratinocytes. The stimulation of beta-endorphin release by AM1241 was inhibited by the CB2 receptor-selective antagonist, AM630, and was not observed in skin from CB2 receptor knockout mice, demonstrating that it is mediated by CB2 receptor. These results suggest that CB2 receptor activation produces antinociception by stimulating the release of beta-endorphin from local cells and that beta-endorphin released acts at beta-opioid receptors to inhibit the responsiveness of primary afferent neurons.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Health Sciences, Pharmacology.; Chemistry, Biochemistry.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmacology and Toxicology
Degree Grantor:
University of Arizona
Advisor:
Malan, T. Philip, Jr.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titlePain-modulating effects of peripheral (CB2) cannabinoid receptorsen_US
dc.creatorIbrahim, Mohab Mohameden_US
dc.contributor.authorIbrahim, Mohab Mohameden_US
dc.date.issued2004en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractCannabinoid receptor agonists diminish responses to painful stimuli. Extensive evidence implicates the CB1, receptor in the production of antinociception, inflammatory hyperalgesia, and peripheral nerve injury-induced sensory hypersensitivity. In previous work included in my masters thesis, our laboratory has demonstrated the capacity of CB2 receptors located outside the central nervous system (CNS) to inhibit acute nociception and inflammatory hyperalgesia. In this thesis, I use AM1241, a CB2 receptor-selective agonist to test the hypothesis that CB2 receptor activation reverses the tactile and thermal hypersensitivity characteristic of neuropathic pain in L5/L6 spinal nerve ligation model. The CB2 receptor-mediated nature of these effects was demonstrated using receptor-selective antagonists, as well as mice deficient in the genes coding for CB1 or CB2 receptors. Experiments using site-specific injections suggest AM1241 acts peripherally at the site of nerve injury and the site of application of the sensory stimulus. The peripheral nature of the effects of AM1241 is consistent with the peripheral distribution of CB 2 receptors. Given the peripheral actions of AM1241, I hypothesized and demonstrated that topical application of AM1241 modulates pain responses. Additionally, I began to examine the mechanisms by which CB2 receptor activation modulates pain responses. The effects of AM1241 were reversed by the opioid receptor antagonist, naloxone and by a sequestering antiserum to beta-endorphin. In addition, the effects of AM1241 were not observed in beta-opioid receptor knockout mice. These results suggest that the endogenous opioid peptide, mu-endorphin plays an essential role in CB2 receptor mediated pain inhibition. Further, AM1241 stimulated release of beta-endorphin from rat skin tissue and cultured human keratinocytes. The stimulation of beta-endorphin release by AM1241 was inhibited by the CB2 receptor-selective antagonist, AM630, and was not observed in skin from CB2 receptor knockout mice, demonstrating that it is mediated by CB2 receptor. These results suggest that CB2 receptor activation produces antinociception by stimulating the release of beta-endorphin from local cells and that beta-endorphin released acts at beta-opioid receptors to inhibit the responsiveness of primary afferent neurons.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectHealth Sciences, Pharmacology.en_US
dc.subjectChemistry, Biochemistry.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacology and Toxicologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorMalan, T. Philip, Jr.en_US
dc.identifier.proquest3132232en_US
dc.identifier.bibrecord.b46708923en_US
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