The overall objective of the research described in this proposal is to elucidate the mechanism of action of morphine and other opiates.
The specific aims of the work proposed in this application are: one, to continue to test our hypothesis that the release of endogenous opiates is an important step in the antinociceptive action of morphine. The data which we have generated thus far indicates that there is an increase in the quantity of known endogenous opiates including met- and leu-enkephalin, Beta-endorphin and dynorphin in dog CSF following an acute injection of an antinociceptive dose (10 mg/kg, s.c.) of morphine. We have also presented evidence that this dose of morphine causes an increase in yet to be identified peptides in CSF which also have opioid activity. Our data also suggests that there is at least one nonpeptide with opioid activity in CSF after morphine. This opioid activity is not due to the presence of morphine in the CSF. Secondly, we propose to study the antinociceptive activity of calcitonin and other endogenous peptides not classified as opiates. Another aspect of these studies will be an investigation of the effects of calcitonin and other endogenous peptides on morphine's actions. Our third specific aim is to elucidate the role of endogenous opioid peptides in sudden infant death syndrome. Preliminary results show that the level of immunoreactivity to Beta-endorphin antibody is significantly higher in babies whose siblings have died of sudden infant death syndrome than in infants of the same age who have had spinal taps for other reasons. The basic information generated from these projects will expand our understanding of pain and its alleviation by opiates, the role of endogenous opiates in normal and abnormal breathing, and the role of peptides not considered opioid as neuromodulators in the actions of endogenous and exogenous opiates.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA001647-13
Application #
3206979
Study Section
(DABB)
Project Start
1976-12-01
Project End
1990-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
13
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Overall Medical
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Bailey, C P; Llorente, J; Gabra, B H et al. (2009) Role of protein kinase C and mu-opioid receptor (MOPr) desensitization in tolerance to morphine in rat locus coeruleus neurons. Eur J Neurosci 29:307-18
Gabra, Bichoy H; Bailey, Chris P; Kelly, Eamonn et al. (2008) Pre-treatment with a PKC or PKA inhibitor prevents the development of morphine tolerance but not physical dependence in mice. Brain Res 1217:70-7
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Gabra, Bichoy H; Smith, Forrest L; Navarro, Hernan A et al. (2008) mGluR5 antagonists that block calcium mobilization in vitro also reverse (S)-3,5-DHPG-induced hyperalgesia and morphine antinociceptive tolerance in vivo. Brain Res 1187:58-66
Stoller, Dawn C; Sim-Selley, Laura J; Smith, Forrest L (2007) Role of kappa and delta opioid receptors in mediating morphine-induced antinociception in morphine-tolerant infant rats. Brain Res 1142:28-36
Smith, Forrest L; Lindsay, Raymond J (2007) Enhancement of bupivacaine local anesthesia with the potassium channel blocker ibutilide. Eur J Pain 11:551-6
Bailey, Chris P; Smith, Forrest L; Kelly, Eamonn et al. (2006) How important is protein kinase C in mu-opioid receptor desensitization and morphine tolerance? Trends Pharmacol Sci 27:558-65
Bernstein, M A; Welch, S P (1999) A method for the determination of activated receptor phosphorylation state following in vivo drug treatment. Brain Res Brain Res Protoc 4:420-4
Bernstein, M A; Welch, S P (1998) Inhibition of protein phosphatases alters the expression of morphine tolerance in mice. Eur J Pharmacol 341:173-7

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