Placenta ingestion by rats enhances y- and n-opioid antinociception, but suppresses A-opioid antinociception



28


J.M. DiPirro, M.B. Kristal / Brain Research 1014 (2004) 22-33

morphine has affinity for both A and y receptors [25], it is
likely that POEF suppression of morphine-induced circling
reflects the inhibition of opioid activity at VTA
A or y sites.
The attenuation of DAMGO antinociception by POEF
ingestion, then, represents a second case in which POEF
inhibits behavior produced by activation of opioid (probably
A) receptors. It is clear, however, that POEF does not inhibit
all
A-related behavior; amniotic fluid ingestion has no
effect on opioid-induced hyperthermia
[1], which is likely
mediated at medial preoptic
A receptors [98].

An important question is whether POEF (during placen-
tophagia) modulates the
A-opioid component of non-anti-
nociceptive processes that are involved in parturitional
behavior. Maternal care of the young, for example, is
disrupted by
A-opioid activity at certain brain sites. In rats
on postpartum day 5, i.c.v. injection of the
A agonist
DAMGO, but not the y agonist DPDPE or the
n agonist
U-50,488, disrupted ongoing maternal behavior (as defined
by latency to retrieve, group, and crouch over pups)
[49].
The data of Experiment 2 demonstrate an inhibitory role for
central opioids in the regulation of maternal behavior that is
specific to the
A receptor. In light of these data, it possible to
hypothesize that POEF, through anti-
A-opioid action (Ex-
periment 2), may contribute to the facilitation of maternal
behavior by attenuating a disruptive opioid influence,
perhaps in the medial preoptic area
[49], while simulta-
neously enhancing the positive motivational aspect of the
stimuli by enhancing opioid activity of non-
A-receptors in
the VTA
[88,89].

5. Experiment 3: K-opioid receptors

The effect of placenta ingestion on the antinociception
produced by the i.c.v. injection of each of four doses of the
n
opioid-preferential agonist spiradoline was tested.

5.1. Method

5.1.1. Subjects

One hundred two virgin female rats served as subjects. In
contrast to Experiments 1 and 2, where rats in all stages of
the estrous cycle were used, in Experiment 3 only rats in
Day 1 or 2 of diestrus on the day of testing were used. Pilot
studies showed that spiradoline effects were very sensitive
to changes in the estrous cycle. This sensitivity has been
demonstrated with other opioids, such as morphine
[35], but
was not present in the current series of studies with either
DAMGO or DPDPE, based on a post hoc examination of
the data.

5.1.2. Design

The design of this experiment was a 2 x 4 between-
subjects factorial: Enhancer (1.0 g placenta or 1.0 g control
substance)
x Dose of n agonist (0, 100, 150, or 200 nmol
spiradoline in 4.0
Al, i.c.v.). Rats were randomly assigned
to one of eight experimental conditions and tested only
once.

5.1.3. Drug

The n-receptor-selective agonist used was ( F )-(5a,7a,
8
h)-3,4-dicloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-(oxas-
piro-[4,5]dec-8-yl]benzeneacetamide monohydrochloride
(spiradoline or U-62,066—purchased from Research Bio-
chemicals International). This drug displays a binding
affinity for the
n-opioid receptor that is 84 times greater
than its affinity for
A and y receptors [6,92]. Spiradoline
was dissolved in 0.02% ascorbic acid and injected within
48 h of entering solution.

5.2. Results and discussion

Of the 102 rats tested in Experiment 3, two rats failed to
eat placenta or beef control during testing, and four rats had
inaccurate cannula placement. Only the data from the
remaining 96 rats were used for further analysis.

5.2.1. POEF and j-mediated antinociception

The effect of POEF ingestion on n-mediated antinoci-
ception is depicted in
Fig. 3. Placenta ingestion significantly
enhanced the response latency produced by the low (100
nmol) dose of spiradoline, lengthening the median response
latency by approximately 30% (placenta Mdn= 15.7 s;
control Mdn= 12.2 s) (v2[1,
n=26]=3.84, p < 0.05). At
the low dose, spiradoline, alone, seems not to have produced
measurable antinociception (subthreshold dose), whereas
spiradoline, in conjunction with placenta ingestion, did
produce measurable antinociception. Placenta ingestion
was without effect on the hotplate latency of rats injected

Fig. 3. Enhancement by placenta ingestion of n-opioid receptor-mediated
antinociception. Female rats in diestrus (Day 1 or 2) were fed 1.0 g placenta
(
.) or control substance (o) 10 min before they were injected with
spiradoline (0, 100, 150, or 200 nmol, i.c.v.). Pain threshold is represented
by median response latency (in seconds) on a 52
jC hotplate test 20 min
after spiradoline injection (n =11-13 rats/group). *Significantly different
from control-fed treatment group at the corresponding spiradoline dose
(
p < 0.05, median test).



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