The Role of N-Methyl-D-Aspartate Receptors in the Release of Adrenocorticotropin by Dynorphin A_1–13

Abstract

We previously reported that dynorphin A_1–13 evokes a significant increase in plasma adrenocorticotropin (ACTH) after intravenous administration in the ovine fetus. This response was not sensitive to naloxone and was regulated differently from the response to U50,488H, a selective ĸ-opioid agonist. NMDA appears to play a role in many of the nonopioid actions of dynorphin. We therefore hypothesized that dynorphin A_1–13 may release ACTH via N-methyl-D-aspartate (NMDA) receptors. To test this hypothesis, we have compared the ACTH response to dynorphin A_1–13 and NMDA in the chronically-instrumented ovine fetus. Our data show that both dynorphin A_1–13 (0.5 mg/kg) and NMDA (4 mg/kg) induced a significant release of immunoreactive ACTH in the late-term ovine fetus. The ACTH response to NMDA was of a smaller magnitude, but of longer duration, when compared to dynorphin A_1–13. The response to both dynorphin A_1–13 and NMDA was significantly attenuated by pretreatment with the noncompetitive NMDA antagonist, MK-801, but was not affected by antagonists of corticotropin-releasing hormone and arginine vasopressin. Finally, the ACTH response to both dynorphin A_1–13 and NMDA were inhibited by dexamethasone. The results of this study indicate a role for NMDA receptors in the action of dynorphin A_1–13, and suggest that NMDA may act directly at the level of the pituitary to release ACTH without the involvement of hypothalamic secretagogues.

Dynorphin Stimulates Corticotropin Release from Mouse Anterior Pituitary AtT-20 Cells through Nonopioid Mechanisms

“…This is contrary to our original hypothesis and is inconsistent with our previous findings in the ovine fetus [5]. The reason behind this discrepancy is not clear, but it may reflect species differences, or a difference between primary cultures of anterior pituitary cells and a tumor cell line.…”

“…Previous studies in the fetal sheep suggested that Dyn A might act directly at the anterior pituitary to release ACTH via NMDA receptors [5]. Dyn is known to be co-localized and to be co-released with CRH and AVP from the hypothalamus [8, 9].…”

“…Another possibility is that the release of ACTH by Dyn A and NMDA may be developmentally regulated. We have found that the ovine fetus does not respond to Dyn A or NMDA prior to 135 days’ gestation [5], and the response is also significantly attenuated in the newborn lamb [unpubl. data].…”

“…We recently reported that the release of ACTH by Dyn in the fetal sheep was blocked by MK-801, a noncompetitive NMDA receptor antagonist. Furthermore, direct administration of NMDA also evoked an increase in plasma ACTH [5]. In contrast to U50488H, antagonists to CRH and AVP had no effect on the response to Dyn A or NMDA [5], suggesting that Dyn A and NMDA may act directly at the anterior pituitary to release ACTH.…”

Sexual Dimorphism and the NMDA Receptor in Alloparental Behavior in Juvenile Prairie Voles (Microtus ochrogaster).

“…However, NMDA receptors are also found in many other brain regions, and the changes we found may be due to a subcortical site of action. For instance, NMDA may play a role in the release of adrenocorticotropin (Szeto, Soong, & Wu, 1999), and corticosterone affects social behavior in this species (DeVries et al, 1996). Consequently, it is possible that the change we found was due to a change in corticosterone release hormone or to some other action in a subcortical region.…”