OR04-3 NEUROKININ B (NKB) AND THE NKB RECEPTOR AGONIST, SENKTIDE, ACT IN THE OVINE ARCUATE NUCLEUS TO PRODUCE DIFFERENT PATTERNS OF LH RELEASE

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR04-GnRH & Gonadotroph Biology & Signaling
Basic/Translational
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 12:00 PM
Room 135 (Moscone Center)
Robert L Goodman*, Katrina L Porter, John M Connors and Stan M Hileman
West Virginia University School of Medicine, Morgantown, WV
Neurokinin B (NKB) is critical for reproductive function in humans, and agonists to the NKB-specific receptor, NK3R, can stimulate LH secretion in several species. Indirect evidence supports the proposal that NKB acts via arcuate nucleus (ARC) kisspeptin neurons to stimulate LH secretion, but most of this work has been done with the NK3R agonist, senktide.  This study had two aims.  First, we directly tested if NKB acts in the ARC, and compared the effects of NKB and senktide on episodic LH secretion in ovariectomized (OVX) ewes. Second, we tested whether afferent input to the ARC from neurons containing orphanin-FQ (OFQ), an inhibitory opioid, controls LH pulses using an antagonist to the OFQ receptor (UFP-101). Ewes (n=6) were OVX and bilateral chronic guide tubes were stereotaxically implanted to target the dorsal edge of the ARC. Starting two weeks later, crystalline drugs, tamped into the lumen of 22 gauge tubing, were administered via the guide tubes. Blood samples were collected for LH measurement every 10 min from 3 h before to 4h  after insertion of tubing that was either empty (controls) or contained NKB, senktide, or UFP-101.  At the end of sampling, microimplants were removed and this protocol was repeated three more times, with four days between replicates, until all ewes received all four treatments in a randomized order.  Histological analysis of microimplantation sites indicated successful targeting of the ARC in 5 of 6 ewes.  In these 5 ewes, clear LH pulses were evident before and during NKB treatment, and NKB significantly decreased interpulse interval (IPI) from 54 ± 2 min (pre) to 42 ± 3 min (during treatment).  In contrast, no change in pulse frequency occurred with control (IPI pre: 55 ± 6; during: 56 ± 5 min) or with UFP-101 (IPI pre: 54 ± 5; during: 55 ± 4 min) treatment. Senktide produced a prolonged increase in LH concentrations lasting 3.5 ± 0.4 hrs, during which discrete LH pulses were difficult to detect. These results demonstrate that NKB can act in the ARC of OVX ewes to increase LH pulse frequency.  Because UFP-101 had no effect, it is unlikely that OFQ plays an important role within the ARC to control pulsatile LH secretion. Local administration of senktide to the ARC clearly produced a different pattern of LH release than NKB.  Whether this pattern reflects continuous GnRH release or very high frequency pulsatile secretion remains to be determined.

Nothing to Disclose: RLG, KLP, JMC, SMH

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: HD017864;HD039916