The discovery of multiple classes of opiate receptors has led to the hypothesis that the diverse actions of opiates may be mediated by different opiate receptors. Available data suggest different, and even opposing, roles for the various receptor subtypes in analgesia, cardiorespiratory, neuroendocrine and metabolic regulation. Studies on the ontogeny of the receptor subtypes have revealed different rates of development for the mu, delta and kappa binding sites in several animal species, resulting in varying proportions of the different binding sites as a function of age. However, the functional implications of the differential ontogeny of these receptor subtypes remain unclear. The primary objective of this proposal is to determine the functional roles of opiate receptor subtypes in early development in the fetal lamb. In this proposal, it is hypothesized that: 1) the mu, delta and kappa receptors mediate different actions on fetal neurobehavioral, cardiorespiratory, neuroendocrine and metabolic regulation; 2) the functional responses to mu, delta and kappa receptor activation change as a function of gestational age; 3) the endogenous opioid peptides exert tonic influence at the various receptor subtypes to modulate neurobehavioral, cardiorespiratory, neuroendocrine and metabolic function. Recent work from our laboratory have already shown that mu and delta receptors exert different actions on neurobehavioral and cardiorespiratory functions in the late-term fetal lamb.
Our specific aims for the next 5 years are as follows: 1) extend these studies to investigate the effects of kappa agonists on fetal EEG, breathing movements, blood pressure and heart rate; 2) determine the effects of selective mu, delta and kappa agonists on plasma ACTH, cortisol, prolactin, growth hormone and vasopressin levels; 3) determine the effects of mu, delta and kappa agonists on blood glucose and lactate levels; 4) compare the response profiles to selective mu, delta and kappa agonists at two gestational ages (100-115d and 125-140d); and 5) ascertain the functional roles of the endogenous opioid peptides by using selective mu, delta and kappa antagonists. The overall experimental plan will include: use of a conscious unanesthetized animal model, examination of multiple pharmacologic functions, incorporation of two gestational age groups, use of highly selective opiate agonists and antagonists, complete dose-response design with vehicle control, and demonstration of response blockade by selective antagonists. The proposed studies will provide new information on the functional roles of opiate receptor subtypes in the fetus, and should be helpful in the design of better analgesics for perinatal use.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Rapaka, Rao
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Schools of Medicine
New York
United States
Zip Code
Tang, Qingbo; Bangaru, Madhavi Latha Yadav; Kostic, Sandra et al. (2012) Ca²?-dependent regulation of Ca²? currents in rat primary afferent neurons: role of CaMKII and the effect of injury. J Neurosci 32:11737-49
Gemes, Geza; Bangaru, Madhavi Latha Yadav; Wu, Hsiang-En et al. (2011) Store-operated Ca2+ entry in sensory neurons: functional role and the effect of painful nerve injury. J Neurosci 31:3536-49
Szeto, Hazel H (2003) Dynorphin and the hypothalamo-pituitary-adrenal axis during fetal development. Life Sci 73:749-58
Szeto, Hazel H; Soong, Yi; Wu, Dunli et al. (2003) Endogenous opioid peptides contribute to antinociceptive potency of intrathecal [Dmt1]DALDA. J Pharmacol Exp Ther 305:696-702
Birk, Alex V; Leno, Endri; Robertson, Hugh D et al. (2003) Interaction between ATP and catecholamines in stimulation of platelet aggregation. Am J Physiol Heart Circ Physiol 284:H619-25
Nardo, Laura; Soong, Yi; Wu, Dunli et al. (2002) Site and mechanism of action of dynorphin A-(1-13) and N-methyl-D-aspartate on ACTH release in fetal sheep. Am J Physiol Endocrinol Metab 282:E1301-7
Birk, Alex V; Bubman, Darya; Broekman, M Johan et al. (2002) Role of a novel soluble nucleotide phospho-hydrolase from sheep plasma in inhibition of platelet reactivity: hemostasis, thrombosis, and vascular biology. J Lab Clin Med 139:116-24
Birk, Alex V; Broekman, M Johan; Gladek, Eva M et al. (2002) Role of extracellular ATP metabolism in regulation of platelet reactivity. J Lab Clin Med 140:166-75
Cheng, P Y; Birk, A V; Gershengorn, M C et al. (2000) Dynorphin stimulates corticotropin release from mouse anterior pituitary AtT-20 cells through nonopioid mechanisms. Neuroendocrinology 71:170-6
Szeto, H H; Soong, Y; Wu, D (1999) The role of N-methyl-D-aspartate receptors in the release of adrenocorticotropin by dynorphin A1-13. Neuroendocrinology 69:28-33

Showing the most recent 10 out of 51 publications