CPDD 72nd Annual Meeting • Scottsdale, Arizona - The College on ...

141
MORPHINE IN COMBINATION WITH METABOTROPIC
GLUTAMATE RECEPTOR ANTAGONISTS IN A MODEL OF
INFLAMMATORY PAIN.
Dana E Daugherty 1 , M J Picker 1 , L A Dykstra 1,2 ; 1 Psychology, University of
North Carolina at Chapel Hill, Chapel Hill, NC, 2 Pharmacology, University of
North Carolina at Chapel Hill, Chapel Hill, NC
Aims: <strong>The</strong> present study examined the effects of the mGluR1 antagonist [(3,4dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexl)-methanone]
(JNJ16259685) and the mGluR5 antagonist 2-methyl-6-(phenyl-ethynyl) pyridine
hydrocholoride (MPEP), alone or in combination with selected doses of
morphine in the capsaicin-induced hyperalgesic tail withdrawal model of inflammatory
pain in rats.
Methods: Baseline latencies to withdraw the tail from a 45°C water bath were
determined in male Fischer 344 rats following capsaicin admininstration to the
tail . After baseline determinations, morphine (0.3-10.0 mg/kg), JNJ16259685
(1.0-3.0 mg/kg), or MPEP (1.0-10.0 mg/kg) were administered alone or in
selected dose combinations 30 min prior to testing. 15 min prior to testing, rats
received 0.3 μg capsaicin into the tail under isoflurane anesthesia, with animals
recovering within 2-3 min. Latencies to withdraw the tail from the 45°C water
bath were recorded 15 min following capsaicin injection.
Results: JNJ16259685 produced no significant antinociceptive effect alone and
did not shift the morphine dose effect curve at any dose tested. Similarly, low
doses of MPEP (1.0-3.0 mg/kg) produced no antinociceptive effect alone and
did not shift the morphine dose effect curve; however, the highest dose of MPEP
(10.0 mg/kg) produced a significant antinociceptive effect alone and a small, but
significant attenuation of the high morphine doses (3.0-10.0 mg/kg).
Conclusions: <strong>The</strong>se results indicate that the effects of mGluR antagonism on
morphine antinociception in an inflammatory pain model depend on the dose
and type of antagonist as well as the dose of morphine.
Financial Support: R01-DA002749 and T32-DA007244.
143
LOPERAMIDE-INDUCED TASTE AVERSIONS IN F344 AND
LEW RATS: ASSESSMENT OF PERIPHERAL OPIOID
ACTIVATION.
Catherine M Davis 1 , J L Cobuzzi 2 , A L Riley 2 ; 1 Psychiatry and Behavioral
Sciences, Division of Behavioral Biology, Johns Hopkins University School of
Medicine, Baltimore, MD, 2 Psychology, American University, Washington, DC
Aims: <strong>The</strong> inbred F344 and LEW rats display strain differences in the aversive
effects of systemically administered morphine, but display no differences in the
aversive effects of centrally administered DAMGO, a selective mu opioid receptor
agonist. <strong>The</strong>se discrepant results suggest that the strain differences in morphine’s
aversive effects between these animals could be a function of differential
activation of peripheral mu opioid receptors.
Methods: To test this hypothesis, male F344 (N = 67) and LEW (N = 67) rats
were conditioned with loperamide, a peripheral mu opioid receptor agonist, in
the CTA design. Animals received saccharin to drink followed by an injection of
loperamide (0, 10, 18 or 32 mg/kg, s.c.; a total of three such pairings).
Results: Repeated-measures ANOVA revealed no strain differences, i.e., loperamide
induced aversions of comparable strength in LEW and F344 rats, suggesting
that peripheral mu opioid activation does not differ between the two
strains. In follow-up assessments in which rats of both strains received saccharin
without a subsequent loperamide injection, only the LEW rats conditioned
with10 mg/kg loperamide extinguished the CTA; extinction was not evident in
any other group.
Conclusions: <strong>The</strong> fact that loperamide induced dose-dependent aversions in
both strains with no significant differences in acquisition of the aversions suggests
that factors other than peripheral opioid activation accounts for the reported
differences in morphine-induced CTA between the two strains (F>L). One
possibility is that the aversive effects of morphine are peripherally mediated and
similar for the F344 and LEW rats. Morphine’s central (rewarding) actions may
be different between F344 and LEW rats and it is this central activity that may
modulate morphine’s perceived aversive effects, i.e., the centrally mediated
rewarding effects of morphine may impact the degree to which it can condition
an aversion in the two strains.
Financial Support: Supported by a grant from the Mellon Foundation to ALR.
<strong>CPDD</strong> <strong>72nd</strong> <strong>Annual</strong> <strong>Meeting</strong> <strong>•</strong> <strong>Scottsdale</strong>, <strong>Arizona</strong>
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142
DISTRESS TOLERANCE AND ADOLESCENT SUBSTANCE
USE PROBLEM SEVERITY.
Stacey B Daughters 1 , S M Gorka 1,2 , C W Lejuez 2 , R M Travers 2 , J Leonard 1 , K
Smith 2 ; 1 Department of Public and Community Health, University of
Maryland, <strong>College</strong> Park, MD, 2 Department of Psychology, University of
Maryland, <strong>College</strong> Park, MD
Aims: <strong>The</strong> problem of substance use in adolescence continues to grow despite
large-scale public health efforts to reduce both its incidence and prevalence. This
is particularly troublesome given that adolescent substance use and especially
misuse often signals future impairments in physical health, mental health and
social and occupational functioning. To enhance prevention efforts, theorists
have attempted to understand factors that contribute to the etiology and maintenance
of substance misuse, with particular emphasis on the role of negative
emotional states. Initial evidence suggests that pre-adolescents with low distress
tolerance, defined as the inability to persist in goal directed activity in the presence
of intense emotional discomfort, are significantly more likely to have used
alcohol in the past year (Daughters et al., 2009). However, limitations of this
study included low levels of past year alcohol use indicative of a pre adolescent
sample, as well as lack of inclusion of a measure of behavioral disinhibition,
which is consistently associated with higher rates of delinquent behavior among
adolescents.
Methods: In attempts to replicate and expand on this finding, we examined the
relationship between distress tolerance, behavioral disinhibition (i.e., impulsivity),
and the total substance use problem index of the Global Appraisal of Individual
Needs (GAINS) scale among a sample of 150 15-17 year old adolescents.
Results: Hierarchical linear regression was used to example the unique and interacting
effects of distress tolerance and impulsivity on substance use total problems.
Findings indicate that among girls, but not boys, the interaction of low distress
tolerance and high levels of impulsivity significantly predict greater
substance use total problems (R2 = .21, F = 6.6, p < .001; B = 0.22, sr2 = .09, p
< .001).
Conclusions: Future research directions and implications for translating this basic
research into effective prevention and intervention programs will be discussed.
Financial Support: NIDA R21DA022741
144
MANUFACTURE, CHARACTERIZATION, AND STABILITY
OF STANDARDIZED MARIJUANA CIGARETTES.
K Davis 1 , Poonam G Pande 1 , B Thomas 1 , S Sabharwal 1 , M McCleary 1 , L
Caddell 1 , P Leahy 1 , M ElSohly 2 ; 1 Analytical Chemistry & Pharmaceutics, RTI
International, Research Triangle Park, NC, 2 University of Mississippi,
University, MS
Aims: <strong>The</strong> NIDA Drug Supply Program requires a constant supply of standardized
marijuana cigarettes at specified potencies for use in scientific research and
clinical studies. <strong>The</strong>se cigarettes are manufactured per current good manufacturing
practices regulations and released per established specifications for Δ9-THC
and moisture content.
Methods: RTI has been manufacturing marijuana cigarettes for NIDA since
1974. <strong>The</strong> marijuana cigarettes are standardized for size and weight. <strong>The</strong> manufacturing
parameters are kept consistent between batches. Potency is controlled
through selective blending of bulk marijuana batches to produce a uniform,
homogeneous lot of starting material for cigarette manufacture. For controls or
placebos, Δ9-THC is extracted to produce plant material with less than 0.1%
Δ9-THC. During manufacture, the cigarettes are tested for weight variation,
moisture by a gravimetric method, and Δ9-THC content by a validated capillary
gas chromatography (CGC) method. Analyses obtained via three extraction procedures
provide profile of the cannabinoid content of cigarettes. Stability of cigarettes
is monitored at ambient, refrigerator, and freezer conditions. At threemonth
intervals, the stored cigarettes are analyzed for Δ9–THC and other
cannabinoids by CGC. <strong>The</strong> quantitative analytical data obtained from these
analyses is examined for trends over time. Data for each batch of marijuana cigarettes
is placed in a FDA Drug Master File and included in IND applications
by NIDA investigators.
Results: <strong>The</strong> analytical data obtained demonstrate that each batch of standardized
marijuana cigarettes meet established specifications for Δ9-THC and moisture
content. <strong>The</strong> cigarettes are found to be stable at frozen conditions.
Conclusions: Standardized marijuana cigarettes manufactured at varying potencies
as required by NIDA, stored under frozen conditions and shipped to NIDA
investigators are of appropriate quality for use in research programs.
Financial Support: By NIDA under a contract to the University of Mississippi
and subcontract to RTI.