Summary
Although kappa-opiate receptors represent an important fraction of the total opiate
receptor capacity in human brain their endocrine function is unknown. We determined
the effects of a kappa-opiate receptor agonist on the secretion of vasopressin, ACTH
and cortisol and on diuresis. The racemic benzomorphan kappa agonist MR 2033 or its
opiate active (-)-isomer, MR 2034, inhibited the release of cortisol and ACTH in 12
trials in a naloxone reversible manner; plasma levels of vasopressin were not altered.
The (+)-isomer, MR2035, did not affect the secretion of cortisol or ACTH.
Surprisingly, in five other subjects large increases were observed in vasopressin,
ACTH and cortisol following the kappa-agonist, which were probably elicited indirectly
by aversive effects of the opioid.
The subjects in whom vasopressin release was not altered by MR 2033 and MR 2034 displayed
large decreases in urine osmolality which were not antagonized by naloxone. The opiate
inactive (+)-isomer, MR 2035, caused no diuretic response. Subjects in whom vasopressin
release was stimulated did not show decreases in urine osmolality indicating that
vasopressin is capable of antagonizing the diuretic action of the kappa-agonist.
Our data show that a kappa-agonist inhibits secretion of cortisol and ACTH by acting
at stereospecific opiate receptors and elicits diuresis by acting at stereospecific,
but naloxone-insensitive non-classical opioid receptors. These data support the concept
that different types of kappa-receptors can be distinguished in man.
Key-Words
Kappa-Opioid
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Kappa-Opiate Receptor
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Benzomorphan
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ACTH
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Cortisol
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Diuresis
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Vasopressin
