Kappa agonist CovX-Bodies

On the basis of opioid-stimulated contraction of dispersed gastric smooth muscle cells it has been suggested that these cells possess opioid receptors of three subtypes: kappa (kappa), mu (mu), and delta (delta). We have used selective peptidase-resistant radioligands, agonists and antagonists, to examine receptor subtypes on dispersed gastric smooth muscle cells from guinea pigs prepared by collagenase digestion. The kappa-agonist U-50488H, the mu-agonist [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAGO), and the delta-agonist [D-Pen2,Pen5]enkephalin (DPDPE) each caused muscle contraction. The concentrations required to caused half-maximal contraction were U50488H (6 pM) greater than DAGO (13 pM) greater than DPDPE (6 nM). The abilities of these agonists to inhibit binding of [3H]U-69593 (kappa-preferring) by 50% were U50488H (43 nM) greater than DAGO (43 microM) greater than DPDPE (200 microM). Their abilities to inhibit binding of [3H]naloxone (mu-preferring) by 50% were DAGO (0.2 microM) greater than U50488H (10 microM) greater than DPDPE (greater than 100 microM). No binding could be detected with the delta-selective ligand [3H]DPDPE. The kappa-preferring antagonist Mr2266 (10 nM) preferentially inhibited contraction stimulated by the kappa-agonist U50488H, and naltrexone (10 nM) (mu-selective antagonist) preferentially inhibited contraction stimulated by the mu-agonist DAGO. ICI 174864 (200 microM; delta-selective antagonist) had no effect on contraction stimulated by mu-, kappa-, or delta-agonists. Contraction stimulated by the delta-agonist DPDPE was inhibited by both kappa- and mu-receptor antagonists. Studies on the effect of the antagonists on binding of [3H]naloxone and [3H]U69593 also provided evidence for kappa- and mu-sites but nor for delta-sites.(ABSTRACT TRUNCATED AT 250 WORDS)

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Examination of the kappa agonist and antagonist properties of opioids in the rat drug discrimination procedure

Behavioural Pharmacology ◽

10.1097/00008877-199511000-00006 ◽

1995 ◽

Vol 6 (7) ◽

pp. 703???717 ◽

Cited By ~ 14

Author(s):

M. A. Smith ◽

M. J. Picker

Keyword(s):

Drug Discrimination ◽

Kappa Agonist ◽

Discrimination Procedure ◽

Agonist And Antagonist

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kappa-Opioid agonist inhibition of osmotically induced AVP release: preferential action at hypothalamic sites

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.270.2.e367 ◽

1996 ◽

Vol 270 (2) ◽

pp. E367-E372 ◽

Cited By ~ 2

Author(s):

N. F. Rossi ◽

D. P. Brooks

Keyword(s):

Potent Inhibitor ◽

Opiate Receptors ◽

Opioid Antagonist ◽

Posterior Pituitary ◽

Opioid Agonist ◽

Kappa Opioid ◽

Water Diuresis ◽

Kappa Agonist ◽

Opioid Agonists ◽

Kappa Opioid Agonist

Although several studies indicate that kappa-opioid agonists induce a water diuresis by inhibiting vasopressin (AVP) secretion, the locus of the kappa-receptors (neurohypophysial vs. hypothalamic) responsible for this effect remains unclear. We have ascertained the effect of the selective kappa-agonist BRL-52656 (BRL) on AVP secretion by using compartmentalized rat hypothalamoneurohypophysial explants in culture. When applied to the hypothalamus, nanomolar concentrations of BRL inhibited osmotically stimulated AVP secretion. This response was blocked by the highly selective kappa-opioid antagonist nor-binaltorphimine (BNI). However, osmotically stimulated AVP release was suppressed at the neurohypophysial site only by 100 nM BRL and was not reversed by BNI but only by naloxone. This dose of BRL, administered to the posterior pituitary compartment, did not appear to act by the agonist gaining access to hypothalamic kappa-opiate receptors, because BNI added to the hypothalamus failed to prevent the inhibition of AVP secretion. The data demonstrate that BRL is a potent inhibitor of osmotically stimulated AVP secretion via activation of kappa-opiate receptors within the hypothalamus, but that higher concentrations of the drug may also stimulate non-kappa-neurohypophysial opiate receptors that suppress AVP release.

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Efficacy of peripheral kappa agonist fedotozine versus placebo in treatment of irritable bowel syndrome

Digestive Diseases and Sciences ◽

10.1007/bf02209014 ◽

1995 ◽

Vol 40 (10) ◽

pp. 2244-2249 ◽

Cited By ~ 94

Author(s):

M. Dapoigny ◽

J. -L. Abitbol ◽

B. Fraitag

Keyword(s):

Irritable Bowel Syndrome ◽

Kappa Agonist ◽

Irritable Bowel

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The effects of the kappa agonist PD-117302 on feeding behaviour in obese and lean Zucker rats

Pharmacology Biochemistry and Behavior ◽

10.1016/0091-3057(88)90369-3 ◽

1988 ◽

Vol 31 (2) ◽

pp. 425-429 ◽

Cited By ~ 7

Author(s):

G.E. Leighton ◽

R.G. Hill ◽

J. Hughes

Keyword(s):

Feeding Behaviour ◽

Zucker Rats ◽

Kappa Agonist

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Meperidine and Alfentanil Do Not Reduce the Gain or Maximum Intensity of Shivering

Anesthesiology ◽

10.1097/00000542-199804000-00003 ◽

1998 ◽

Vol 88 (4) ◽

pp. 858-865 ◽

Cited By ~ 36

Author(s):

Takehiko Ikeda ◽

Daniel I. Sessler ◽

Farzin Tayefeh ◽

Chiharu Negishi ◽

Minang Turakhia ◽

...

Keyword(s):

Oxygen Consumption ◽

Core Temperature ◽

Maximum Intensity ◽

Intensity Increase ◽

Temperature Deviation ◽

Kappa Agonist ◽

Target Plasma ◽

Opioid Administration ◽

Venous Infusion ◽

Lactated Ringer's Solution

Background Thermoregulatory shivering can be characterized by its threshold (triggering core temperature), gain (incremental intensity increase with further core temperature deviation), and maximum intensity. Meperidine (a combined mu- and kappa-agonist) treats shivering better than equianalgesic doses of pure mu-opioid agonists. Meperidine's special antishivering action is mediated, at least in part, by a disproportionate decrease in the shivering threshold. That is, meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold, whereas alfentanil (a pure mu-agonist) decreases the vasoconstriction and shivering thresholds comparably. However, reductions in the gain or maximum shivering intensity might also contribute to the clinical efficacy of meperidine. Accordingly, we tested the hypothesis that meperidine reduces the gain and maximum intensity of shivering much more than alfentanil does. Methods Ten volunteers were each studied on three separate days: (1) control (no drug); (2) a target total plasma meperidine concentration of 1.2 microg/ml; and (3) a target plasma alfentanil concentration of 0.2 microg/ml. Skin temperatures were maintained near 31 degrees C, and core temperatures were decreased by central-venous infusion of cold lactated Ringer's solution until maximum shivering intensity was observed. Shivering was evaluated using oxygen consumption and electromyography. A sustained increase in oxygen consumption identified the shivering threshold. The gain of shivering was calculated as the slope of the oxygen consumption versus core temperature regression, and as the slope of electromyographic intensity versus core temperature regression. Results Meperidine and alfentanil administration significantly decreased the shivering thresholds. However, neither meperidine nor alfentanil reduced the gain of shivering, as determined by either oxygen consumption or electromyography. Opioid administration also failed to significantly decrease the maximum intensity of shivering. Conclusions The authors could not confirm the hypothesis that meperidine reduces the gain or maximum intensity of shivering more than alfentanil does. These results suggest that meperidine's special antishivering effect is primarily mediated by a disproportionate reduction in the shivering threshold.

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