During gestation, in laboratory animals and women, maternal spinal opioid analgesic systems are activated. This analgesia is mediated by a spinal cord dynorphin/kappa and enkephalin/delta (delta-1 and delta-2) opioid system. One underlying objective of the proposed research is to elucidate the relationship between the multiple spinal opioid analgesic systems that comprise the analgesia of pregnancy. This proposal is also designed to determine the biochemical changes that underlie the adaptation of spinal dynorphin neurons to the increased demands of pregnancy. The specific objects are to (1) Determine if the analgesia of pregnancy is comprised of the sum of separate, independent spinal cord analgesic systems or if it requires their concomitant activation. (2) Determine if gestational-related antinociception involves the modulation of spinal cord opiate receptors.
This aim will utilize opiate receptor immunohistochemistry and autoradiography. (3) Determine the spectrum of dynorphin intermediates that are present in the spinal cord of pregnant and non-pregnant rats and identify those whose concentration is (are) modulated (decreased) during late gestation. (4) Determine whether or not the precursor processing endoproteases PC1 and PC2 are modulated in maternal spinal cord during pregnancy. This study will involve a quantitative comparison of PC1 and PC2 mRNA and PC1 and PC2 enzyme protein in spinal cord obtained from pregnant and non-pregnant rats. (5) Determine the effect of simulating the pregnancy blood concentration profile of 17-beta-estradiol and progesterone on spinal cord dynorphin precursor content and the hormone precursor processing enzymes PC1 and PC2. This research could have direct relevance to the clinical management of the pain of pregnancy and childbirth. Elucidation of the components of the intrinsic pain-attenuating opioid system(s) that are activated during gestation could provide a basis for their manipulation for medicinal purposes. Identification of changes in a particular receptor type or subtype could provide a rationale for the development of more selective drugs for use in labor and delivery. Such information should also heighten awareness of the influence of gender on intrinsic pain attenuating mechanisms. Since stress and exogenous opioids can impact on immune function, a better understanding of how endorphin systems are activated during gestation could ultimately be relevant to treating aids in pregnant women. Finally, it should be noted that during pregnancy, there occurs a sustained activation of intrinsic opioid analgesic activity without the appearance of dependence formation. Thus, the means by which and the combinations in which spinal opioid systems are activated in response to the 'stress' of pregnancy and the underlying adaptive biochemical processes utilized by them under this condition could be relevant to understanding opioid addictive processes in general.
