The Study of the Effect of Drugs of Abuse on Protein Kinase A Activity in Mouse Brain and Spinal Cord

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1 Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2005 The Study of the Effect of Drugs of Abuse on Protein Kinase A Activity in Mouse Brain and Spinal Cord George D. Dalton Virginia Commonwealth University Follow this and additional works at: Part of the Medical Pharmacology Commons The Author Downloaded from This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact libcompass@vcu.edu.

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6 iv Materials Methods of handling mice Surgical implantation of morphine pellets Chronic treatment with A9-THC Intracerebroventricular injections Intrathecal injections Models of morphine antinociceptive tolerance The tail-flick test 33 Reversal of morphine tolerance and i.c.v. injections scheme Potency and selectivity of PKA inhibitors Measurement of PKA activity 35 Activation of PKA by Sp-8-Br-CAMPS Data analysis of PKA activity The correlation of the reversal of morphine antinociceptive tolerance and the inhibition of neuronal Protein Kinase A activity by a Protein Kinase A... inhibitor Background 39 Results Discussion The effect of the level of morphine and A9-THC antinociceptive Tolerance on Protein Kinase A activity in mouse brain and spinal cord Background Results Discussion... 80

7 The effect of the duration of morphine antinociceptive tolerance on Protein Kinase A activity in mouse brain and spinal cord Background Results Discussion 103 General Discussion List of References. 121

8 LIST OF TABLES Table Page 1. Opioid receptor ligands The reversal of morphine antinociceptive tolerance by PKI-(6-22)-amide and PKI-Myr-(14-22)-amide In vitro effect of PKI-(6-22)-amide and PKI-Myr-(14-22)-amide on Protein Kinase A activity in cytosolic and particulate fractions in mouse brain and spinal cord Effect of i.c.v. administration of PKI-(6-22)-amide and PKI-Myr-(14-22)- amide on Protein Kinase A activity in cytosolic and particulate fractions of drug-nai've mouse thalamus and periaqueductal gray Effect of i.c.v. administration of PKI-(6-22)-amide and PKI-Myr-(14-22)- amide on Protein Kinase A activity in cytosolic and particulate fractions of drug-nai've mouse medulla and lumbar spinal cord Effect of i.c.v. administration of PKI-(6-22)-amide and PKI-Myr-(14-22)- amide on Protein Kinase A activity in cytosolic and particulate fractions of 3-day morphine tolerant mouse thalamus and periaqueductal gray Effect of i.c.v. administration of PKI-(6-22)-amide and PKI-Myr-(14-22)- amide on Protein Kinase A activity in cytosolic and particulate fractions of 3-day morphine tolerant mouse medulla and lumbar spinal cord Measurement of basal and total cytosolic Protein Kinase A activity in drug-nai've mouse thalamus and periaqueductal gray immediately following the i.c.v. administration of PKI-(6-22)-amide and PKI-Myr-(14-22)-amide Induction of tolerance to the antinociceptive effects of A'-THC Effects of chronic treatment with A'-THC on cytosolic Protein Kinase A activity in various mouse brain regions and lumbar spinal cord... 73

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12 Abstract THE STUDY OF THE EFFECT OF DRUGS OF ABUSE ON PROTEIN KINASE A ACTIVITY IN MOUSE BRAIN AND SPINAL CORD. By George D. Dalton, Ph.D. A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. Virginia Commonwealth University, Dr. William L. Dewey, Professor, Department of Pharmacology & Toxicology Morphine and A9-THC are drugs that produce analgesia and rewarding effects. However, chronic treatment with morphine and a9-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 A~-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 a9-thc antinociceptive tolerance. Male Swiss Webster mice were treated chronically with morphine or A~-THC and the warm-water tail-flick test was used to assess antinociception. These studies revealed that the level and the duration of morphine antinociceptive tolerance both influenced whether

13 PKA activity was increased in mouse brain and spinal cord. Cytosolic PKA activity was increased in the thalamus of 3-day morphine-tolerant mice expressing a 45-fold level of tolerance, but not in mice that expressed a 10-fold level of tolerance. In addition, cytosolic PKA activity was increased in the lumbar spinal cord (LSC) of 15-day morphine-tolerant mice. However, chronic treatment with A9-THC had no effect on neuronal PKA activity even in mice that expressed a high level of antinociceptive tolerance. The absence of an effect of chronic treatment with A9-THC on neuronal PKA activity was supported by the development of a positive control in which the PKA activator Sp-8-Br-CAMPS was administered intracerebroventricularly (i.c.v.) and intrathecally (i.t.) in drug-nayve mice and increases in PKA activity were observed in several brain regions and LSC. Finally, the i.c.v. injection of two peptide fragments of native Protein Kinase A inhibitor (PKI) peptide, PKI-(6-22)-amide and PKI-(Myr )- amide, significantly reversed antinociceptive tolerance in mice treated chronically with morphine. PKI-(6-22)-amide (i.c.v.) also inhibited PKA activity in brain regions (thalamus, periaqueductal gray (PAG), and medulla) and LSC, which studies have shown play a role in morphine-induced analgesia. Moreover, PKI-(6-22)-amide reduced the increase in PKA activity in thalamus and LSC observed with chronic morphine treatment. Overall, these studies provide evidence that PKA plays a role in morphine tolerance, but not A~-THC tolerance at the doses and times tested.

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