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J.M. DiPirro, M.B. Kristal / Brain Research 1014 (2004) 22-33
reported here. In dose ranges comparable to those used in
the present study, opioid agonists administered i.c.v. affect
thermoregulatory processes in a receptor-specific way, lead-
ing to a pronounced effect on body core temperature (i.e., A:
hyperthermia; n: hypothermia; y: no clear effect) [5,29].
However, it is improbable that the POEF-induced changes
in response latency reported here after DAMGO or spirado-
line injection reflect such a temperature alteration. (1) There
is indirect evidence that hotplate latencies are not affected
by changes in body temperature (e.g., see Ref. [2]). (2)
DAMGO-induced alterations in body temperature are insig-
nificant or still slight at post-injection times that correspond
to the time of antinociception measurement in the present
study [85]. Although spiradoline has been reported to be
hyperthermic [5], the effects are not characterized well
enough to make such a comparison.
Motor effects induced by opioids or POEF represent a
potential confound in the assessment of nociceptive thresh-
old in the present study [55,56]. However, in no instance
were motor effects readily apparent after opioid treatment,
except in Experiment 1. Here, rats treated with the highest
dose of DPDPE and POEF showed circling and elevations
in paw-lick/jump latency. However, POEF-induced eleva-
tions in response latency were also evident at a dose of
DPDPE (62 nmol) that had no effect on circling.
At this point, any conclusion about the involvement of a
particular brain site in the POEF effect is purely conjectural.
However, because the effect of ingested POEF apparently
affects the CNS via vagal afferent information, the CNS
sites of action are likely limited to the areas supplied by
input from the nucleus tractus solitarius (NTS). There is
indirect evidence [18,90] that POEF can influence non-
antinociceptive opioid activity at multiple sites: the VTA,
at which POEF inhibits morphine-induced contralateral
circling [90], and the caudate nucleus [14], at which,
presumably, POEF enhances DPDPE-induced circling (Ex-
periment 1). In a similar fashion, POEF might influence
antinociceptive opioid activity at more than one brain locus.
During late pregnancy and parturition, changes in hor-
monal and sensory aspects of maternal physiology induce a
significant increase in pain threshold [11,15,33,53]. Opioid
mechanisms play a pivotal role in the mediation of this
effect [23,78], and provide, presumably, the endogenous
analgesic substrate(s) for ingested POEF at parturition [45].
Pregnancy is associated with elevated levels of all three
classes of opioid peptides (i.e., enkephalin, h-endorphin,
and dynorphin) and with increased numbers of opioid
receptors (i.e., A receptor) in several brain sites [7,21,
26,68,79,95]. However, to date, little is known of opioid
changes in many specific brain areas, especially antinoci-
ception-processing sites (where neural input from ingested
POEF likely acts).
At the spinal level, opioid changes in late pregnancy
have been investigated more extensively and the results
indicate that spinal-opioid mediation of pregnancy-mediated
analgesia is specific to y and n systems [16,17]. Consistent
with this pattern of opioid receptor involvement are data
showing that elevated pain-response thresholds evident
during pregnancy are associated with enhancement in the
activity of endogenous ligands of the y (enkephalin) and n
(dynorphin) receptors [33,37,74]. However, because the
opioid receptor-specific nature of POEF action has only
been studied at the supraspinal level, the significance of this
relationship is not yet clear.
At the present time, the standard analgesic for the
treatment of chronic pain is morphine, an only slightly
selective (A) opioid agonist [64]. Although narcotics such
as morphine typically generate analgesia that is both robust
and lasting, they also induce a constellation of undesirable
side effects, including the potential for abuse, decreased
gastrointestinal motility, sedation, nausea, vomiting, and
potentially life-threatening respiratory depression [48,58].
Given the potent opioid-enhancing properties of POEF, it is
reasonable to suggest that using POEF as an opioid-analge-
sic adjuvant might be an effective pain-management strat-
egy, and might offer advantages over standard narcotic
treatment. For example, because POEF would presumably
enhance the potency of a simultaneously administered
opiate drug, the dose necessary to obtain the desired level
of pain relief would be lower if POEF were given in
combination with the opiate than if the opiate were given
alone [20]. Therefore, because the severity and number of
side effects are related to the dose of opiate, among other
factors, POEF, if used as an analgesia enhancer, would
likely minimize the side effects that are normally associated
with a particular level of opiate analgesia. This model has
already been demonstrated: placenta ingestion in conjunc-
tion with a subthreshold dose of morphine was shown to
produce the same amount of antinociception as an optimum
dose of morphine in rats. However, the optimum dose of
morphine, when administered alone, disrupted ongoing
maternal behavior, whereas the subthreshold dose in con-
junction with placenta ingestion did not [88].
The complex nature of POEF action on antinociception
produced at different opioid receptor types makes it possible
that POEF induces an optimal combination of receptor-
specific effects: the inhibition of A-mediated side effects
and the facilitation of intended y and n receptor analgesic
effects. That POEF enhances antinociception produced by
the activation of n-opioid receptors may be particularly
relevant to the treatment of pain in women [22]. As
analgesics, A-acting opioids are generally considered to be
far superior to n- and y-acting opioids. However, this
conclusion is based largely on studies using males as
subjects (because few comparable studies exist in women),
so it may not apply equally well to both sexes.
7. Conclusion
The results of these experiments show that ingestion
of POEF, a component of afterbirth tissues, exerts a