University of North Carolina, Chapel Hill, NC

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Stop Animal Exploitation NOW!
S. A. E. N.
"Exposing the truth to wipe out animal experimentation"

Government Grants Promoting Cruelty to Animals

University of North Carolina, Chapel Hill, NC

LINDA A. DYKSTRA - Primate Testing - 2006

Grant Number: 5R01DA002749-29
Project Title: Opioid Analgesics: Pharmacological & Behavioral Factors
PI Information: PROFESSOR LINDA A. DYKSTRA, ldykstra@unc.edu 

Abstract: DESCRIPTION (provided by applicant): There is growing evidence that the N-methyl-D-aspartate (NMDA) class of the glutamate receptor modulates the effects of a number of drugs of abuse. Therefore, it is likely that a deeper understanding of interactions of the NMDA system with drugs of abuse will inform the search for treatment interventions, both in relationship to drug dependence and pain modulation. The proposed experiments explore the mechanisms underlying interactions between the NMDA system and opioid analgesics using an integrative strategy that combines genetic, pharmacological and behavioral approaches. The genetic approach employs an animal model of NMDA deficiency that consists of partial deletion of the gene encoding the essential NR1 subunit of the NMDA receptor (NR1-/- mice). The pharmacological approach explores interactions between drugs of abuse and a range of NMDA antagonists in mice of the C57BL/6 background strain. Both the genetic and the pharmacological approaches are used to investigate several prominent behavioral effects of opioid analgesics, namely their antinociceptive, conditioned and reinforcing effects. Specific Aim 1 examines the role of NMDA receptors in opioid antinociception and tolerance, employing two different antinociceptive assays: the hot plate procedure and the tail withdrawal procedure. Specific Aim 2 investigates the role of NMDA receptors in the conditioned effects of morphine and other opioid analgesics using the conditioned place preference procedure (CPP) and Specific Aim 3 investigates in the reinforcing effects of opioid agonists using a drug self-administration procedure. Preliminary experiments indicate the feasibility of using these approaches in our own laboratory. Collectively, the specific aims test the hypothesis that the antinociceptive and reinforcing effects of morphine and other opioid analgesics are altered in NR1-/- mice as compared to WT controls and that morphine's effects are altered by the administration of selective NMDA antagonists in two background strains of mice, C57BL/6 and 129/SvEv.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
NMDA receptor, analgesic, drug abuse, neuropharmacology, neuroregulation, opiate alkaloid, protein structure function, psychopharmacology conditioning, dextromethorphan, dizocilpine, drug tolerance, morphine, neuropsychology, neurotransmitter antagonist, pain, reinforcer, self medication animal genetic material tag, behavior test, genetically modified animal, laboratory mouse

Institution:
UNIVERSITY OF NORTH CAROLINA CHAPEL HILL
Office of Sponsored Research
CHAPEL HILL, NC 27599
Fiscal Year: 2006
Department: NONE
Project Start: 01-SEP-1977
Project End: 31-DEC-2009
ICD: NATIONAL INSTITUTE ON DRUG ABUSE
IRG: NMB

Vol. 300, Issue 2, 435-441, February 2002

Dextromethorphan Potentiates the Antinociceptive Effects of Morphine and the -Opioid Agonist SNC80 in Squirrel Monkeys

Richard M. Allen, Arthur L. Granger and Linda A. Dykstra

Departments of Psychology (R.M.A., A.L.G., L.A.D.) and Pharmacology (L.A.D.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Animals.

Four adult male squirrel monkeys (Saimiri sciureus) weighing between 0.70 and 0.95 kg were housed in pairs in a colony room with a 12-h light/dark cycle. All monkeys had continuous access to water, were maintained on a high-protein monkey diet, and were given fresh fruit and nuts daily. All of the monkeys had previous experience with the titration procedure and had received various opioid compounds but had not received drugs for at least 30 days before the start of the present experiment.

Apparatus.

During experimental sessions, each monkey sat in a Plexiglas chair and was held in place by a waist support with its tail secured by a small stock (see Dykstra, 1985 ). The tail was coated with EKG Sol, a noncorrosive electrode paste (Graphics Control Medical Products Division, Buffalo, NY), to provide a low-resistance electrical contact. Electric shock (110 V a.c., 60 Hz) was delivered through two hinged brass plates that rested on a shaved portion of the tail.
Each chair was enclosed within a ventilated, sound-attenuating chamber and was illuminated by a 10-W white houselight during experimental sessions. A lever was mounted on the right side of the front panel, 8.5 cm above the waist plate and 4.0 cm from the right side wall. During experimental sessions, presses on the lever with a downward force of 0.15 newton produced an audible click and were recorded as responses. White noise was presented continuously both inside the chamber and throughout the experimental room. Experimental events, including control of shock intensity, were controlled using Med Associates software and hardware (St. Albans, VT) through a microcomputer located in the adjacent room.

Behavioral Procedure.
A shock titration procedure nearly identical to that described by Dykstra (1985) was used. In each session, periods during which an FR 5 schedule of shock titration was in effect alternated with periods of blackout. Each FR 5 titration period began with the illumination of the house light and presentation of 0.01-mA shock. Shock intensity increased from 0.01 to 2.0 mA in 30 increments. Completion of the FR 5 requirement at a given shock intensity initiated a time-out during which shock was off and the house light remained illuminated. After the 15-s time-out, the shock resumed at the next lower intensity. If a monkey failed to complete the FR 5 during 15 s at a given shock intensity, the intensity increased by one increment and the response requirement was reset to 5. The FR 5 titration periods usually lasted 15 min. An FR 5 period terminated automatically, however, if the shock intensity rose to the peak intensity of 2.0 mA and the FR 5 requirement was not completed during any of five consecutive 15-s periods. During the blackouts that separated the FR 5 titration periods, the chamber was dark, no shock was delivered, and lever presses had no programmed consequences. Blackouts lasted 20 min. Each session began with an FR 5 titration period and ended after completion of five FR 5 periods. 

Please email:  LINDA A. DYKSTRA, ldykstra@unc.edu to protest the inhumane use of animals in this experiment. We would also love to know about your efforts with this cause: saen@saenonline.org

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Rats, mice, birds, amphibians and other animals have been excluded from coverage by the Animal Welfare Act. Therefore research facility reports do not include these animals. As a result of this situation, a blank report, or one with few animals listed, does not mean that a facility has not performed experiments on non-reportable animals. A blank form does mean that the facility in question has not used covered animals (primates, dogs, cats, rabbits, guinea pigs, hamsters, pigs, sheep, goats, etc.). Rats and mice alone are believed to comprise over 90% of the animals used in experimentation. Therefore the majority of animals used at research facilities are not even counted.

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