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A Two-Step Mechanism by Which Corticotropin- Releasing Hormone Releases Hypothalamic β-Endorphin: The Role of Vasopressin and G-Proteins^*

Department of Neuropharmacology, Max Planck Institute for Psychiatry, D-8033 Planegg/Martinsried Federal Republic of Germany
Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians- University, D-8000 Munchen 22 Federal Republic of Germany

Address requests for reprints to: Dr. G. Burns, Department of Neuropharmacology, Max Planck Institute for Psychiatry, Am Klopferspitz 18a, D-8033 Planegg/Martinsried, Federal Republic of Germany.

Abstract

It is well established that in the pituitary gland corticotropin-releasing hormone (CRH) stimulates the release of β-endorphin (β-E) via a cAMP-linked mechanism. Studies of the mechanisms underlying the CRH stimulation of β-E release from rat hypothalamic slices perifused in vitro are reported in this paper. The data indicate that both a cAMP-dependent and non-cAMP-dependent mechanism mediate the action of CRH in the hypothalamus.

The presence of a cAMP-linked mechanism was suggested by the finding that cholera toxin (0.1-10 nM) and forskolin (2.5 x 10^–6 M), both of which act to raise intracellular cAMP levels, stimulated the release of β-E. In both cases, no further stimulation was seen upon addition of CRH (10^–8 M). However, it was also found that preincubation of the tissue with pertussis toxin (PTX; 100 ng/ml) prevented both the CRH- and forskolinstimulated release of β-E. This indicated that, in addition to the cAMP-linked mechanism, a further messenger system which is connected to a PTX-sensitive G-protein may also play a role. The latter observation also implied that a further substance, which utilizes a separate second messenger system, might be involved in the CRH stimulation of β-E release. In this regard the role of arginine vasopressin (AVP) was investigated due to the known interaction between CRH and AVP in the pituitary gland. AVP (10^–12 to 10^–6 M) itself potently and dose-dependently stimulated β-E release, producing a maximal increase of 220% above basal levels. The AVP-induced release of β-E was abolished in PTX-pretreated hypothalami.

The apparently obligatory requirement of AVP for the CRHstimulation of β-E release was illustrated by the finding that blockade of AVP receptors using the AVP antagonist d(CH₂)₆ [Tyr(OEt)²,Val⁴]-AVP almost completely attenuated the CRHstimulated release of β-E. Furthermore, in the presence of a high concentration of AVP (10^–6 M) no further stimulation of release was seen with CRH (10^–8 M).

These data therefore strongly indicate that CRH acts via the intermediacy of AVP to release β-E from hypothalamic slices in vitro and that two separate second messenger systems are involved: a cAMP-linked mechanism connected to a cholera toxin-sensitive G-protein (CRH) and a second system linked to a PTX-sensitive G-protein (AVP).

Footnotes

^* This work was supported in part by Grant SFB 220 from the Deutsche Forschungsgemeinschaft.

Received February 27, 1989.

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