CGRP is involved in a variety of stress responses. Central administration of CGRP causes fear related behaviour, activates the sympathetic system and the hypothalamo-pituitary-adrenal (HPA) axis, specially enhancing corticosterone release. CRH antiserum blocks the CGRP-induced rise in corticosterone (Kovacs et al. 1995). CRH, which is central to the HPA axis, plays a pivotal role in stress-induced suppression of pulsatile LH secretion. The aims of the present study were to test the hypothesis that CGRP suppresses LH pulses and to determine whether CRH mediates this response.

Ovariectomized (ketamine, 100 mg kg^-1, ip) Wistar rats were implanted with intracerebroventricular (icv) and intravenous (iv) cannulae (ketamine, 100 mg kg^-1, ip). Blood samples (25µl) were collected every 5 min for 6 h and assayed for LH. After 2 h of sampling CGRP (75, 400, or 1200 pmol) or artificial cerebrospinal fluid (4µl) were administered by icv injection (n = 6-12). In addition, CGRP (400 pmol) was co-administered icv with the CGRP antagonist (CGRP_8-37, 1 nmol, n = 8) or CRH antagonist (α-helical CRF_9-41, 26 nmol, n = 11). Finally rats were given 2 nmol CGRP_8-37 and 10 min later 0.5 U kg^-1 insulin was given iv to induce hypoglycaemia; a stress known to suppress LH (Cates & O’Byrne, 2000). Animals were humanely killed.

I.C.V. infusions of CGRP induce a dose dependant suppression of LH pulses. 400 pmol CGRP significantly (paired Student’s t-test, P < 0.05) increased LH pulse interval from 29 ± 3 min (mean ± S.E.M.) before to 38 ± 4 min after treatment. The higher dose (1200 pmol CGRP) abolished LH pulses for the duration of the 4 h post-treatment period. The CGRP_8-37 blocked the inhibitory effect of CGRP, whilst the CRH antagonist blocked the inhibitory effect of CGRP on LH pulses for the first 2 h post-infusion. Furthermore, CGRP_8-37 completely blocked the hypoglycaemic stress-induced suppression of LH pulses. The expression of FOS immunoreactivity following icv CGRP (1.2 nmol) was found to be particularly intense within the paraventricular nucleus (PVN) and the medial preoptic area.

These results suggest that central CGRP suppresses the gonadotropin releasing hormone pulse generator and is mediated, at least in part, by CRH. The ability of a CGRP antagonist to block the effects of hypoglycaemic stress on the pulsatile release of LH indicates that CGRP may be physiologically relevant in mediating metabolic stressors. Neuronal activation in both the PVN and the preoptic area identifies these as brain regions which may be critical in the response to central CGRP.

This work was supported by the Guy’s & St Thomas’s Charitable Foundation and Wellcome Trust.