Morphine Inhibits the Pituitary-Adrenal Response to Ovine Corticotropin-Releasing Hormone in Normal Subjects*

Abstract

To determine the locus of opiate modulation of ACTH secretion, 11 normal subjects were given ovine corticotropin-releasing hormone (CRH) 30 min after receiving either placebo or morphine sulfate. Plasma ACTH, cortisol, arginine vasopressin (AVP), epinephrine, norepinephrine, and CRH were measured 30 min before and up to 150 min after CRH administration. Morphine blunted the ACTH response for the first 60 min and cortisol response for the first 90 min after CRH administration. Morphine did not lower arginine vasopressin or catecholamine levels. To determine whether morphine's effect on ACTH and cortisol was due to a direct action on the corticotroph cell, dispersed rat pituitary cells were perifused with medium containing 1 microgram/ml morphine sulfate or medium alone. Morphine had no effect on the ACTH response of these cells to 10 nM CRH pulses. Similarly, morphine had no effect on ACTH production by dispersed rat pituitary cells in monolayer culture in response to 90- and 180-min incubations with 5 nM CRH. We conclude that morphine blunts the early response of the pituitary gland to CRH in vivo. Based on the lack of a direct effect of morphine on rat pituitary cells in vitro, we postulate that morphine given in vivo may modulate the pituitary ACTH response to CRH through other suprapituitary factors.

Inferior petrosal sinus sampling in healthy subjects reveals a unilateral corticotropin-releasing hormone-induced arginine vasopressin release associated with ipsilateral adrenocorticotropin secretion.

“…To our knowledge, this is the first study to demonstrate a stimulatory effect of CRH on petrosal AVP concentrations in normal human subjects. Despite evidence that CRH stimulates plasma AVP and OT in animals (24-27), a number of studies measuring peripheral AVP have failed to demonstrate such an effect in humans (28)(29)(30). In the present study, however, CRH-induced AVP secretion was detectable only in the dominant IPS, before the dilution of pituitary effluent by the systemic circulation.…”

“…Although CRH has been shown to stimulate magnocellular AVP and OT from the isolated rat neurointermediate pituitary (45,46), this mechanism is not likely to pertain to humans in whom the intermediate lobe is rudimentary. However, it may explain the observed clear stimulatory effect of CRH on peripheral plasma AVP and OT in animals (24-27) and the absence of an effect in humans (28)(29)(30). AVP terminals in the ME are of parvocellular origin; however, we believe that the observed AVP elevation in the dominant petrosal sinus is predominantly of magnocellular origin, for the following reasons: The amount of parvocellular AVP is at least one order of magnitude lower than that released by magnocellular neurons (47).…”

“…In addition to the well established synergistic effects of CRH and AVP on the release of ACTH (6)(7)(8), CRH administration at a nonhypotensive dose has been shown to stimulate plasma AVP (24-26) and OT (27) in animals, but not in humans (28)(29)(30). Recently, Nussey et al reported lateralized AVP and OT secretion into the IPS of patients with Cushing disease after administration of CRH, without a concomitant change in peripheral AVP or OT levels (31).…”

Serum Cortisol Secretion During Heroin Abstinence Is Elevated Only Nocturnally

“…Indeed, the widespread distributions of these receptors confirm the broad brain effects of the HPA response to psychological stress (4). administered with significantly lower cortisol levels than controls (1,(6)(7)(8). In non-heroinusing individuals, hypocortisolism is observed after administration of codeine or the metenkephalin analog FK 33-824 (9,10).…”

Corticotrophin Releasing Factor in Man and Its Measurement: A Review

“…However, another study using the ovine peptide merely showed an additive effect of CRF and endogenous AVP (Rittmaster et al, 1986) and patients with diabetes insipidus exhibited normal responses to C R F (Schurmeyer et al, 1984a). Insulin-induced hypoglycaemia results in greater ACTH and cortisol release than can be achieved by the simultaneous administration of C R F and AVP, and even higher levels of plasma ACTH are found after pyrogen administration or during surgery.…”