Kappa Opioid Receptor Agonist U50 Research Articles

Dietary Modulation Of Mu And Kappa Opioid Receptor-mediated Analgesia

Research has demonstrated that intake of palatable carbohydrates and fats enhanced morphine-induced analgesia (MIA) in Sprague–Dawley rats. To determine if the effects of palatable foods on nociceptive responses would generalize to other strains of animals and other opioid agonists, the present experiments investigated whether intake of palatable foods would: a) alter MIA in Long–Evans rats, and b) alter analgesia produced by drugs acting at kappa opioid receptors. In experiment 1, adult male Long–Evans rats were fed Purina chow alone or chow and either a 32% sucrose solution, a 0.15% saccharin solution, or hydrogenated vegetable fat. Using a tail-flick apparatus, nociceptive responses, measured as percent maximal possible effect (%MPE), were examined after morphine administration [0.0, 1.0, 3.0, and 6.0 mg/kg subcutaneously (SC)]. %MPEs varied directly as a function of dose and were significantly greater for rats fed chow and either sucrose or fat than for rats fed chow alone or chow and saccharin. Experiment 2 compared the analgesic effect of the kappa opioid receptor agonist U50,488H (0, 5.0, 10.0, and 20.0 mg/kg SC) in rats fed chow alone or chow and a 32% sucrose solution. Administration of U50,488H led to analgesia. However, %MPEs did not vary directly as a function of dose. %MPEs of rats fed chow and sucrose were significantly greater than those of rats fed chow alone after injections of 10.0 and 20.0 mg/kg U50,488H. Experiment 3 compared the analgesic effect of U50,488H (5.0, 10.0, 15.0, and 20.0 mg/kg SC) in rats fed chow alone or chow and either a 0.15% saccharin solution or hydrogenated vegetable fat. Administration of U50,488H led to analgesia. However, %MPEs did not vary directly as a function of dose or as a function of diet. %MPEs of rats fed chow and fat were significantly greater than those of rats fed chow alone after injection of 5.0 mg/kg U50,488H.

Opioid receptor-mediated control of acetylcholine release in human neocortex tissue.

The effects of various opioid receptor agonists and antagonists on evoked acetylcholine release were studied in slices of human neocortex prelabelled with [3H]-choline, superfused and depolarized electrically (2 min, 3 Hz, 2 ms, 24 mA) or by K+ (20 mM). The delta-opioid receptor agonist DPDPE and the kappa-opioid receptor agonist U50488 reduced the evoked [3H]-overflow (acetylcholine release) in a concentration-dependent fashion; the delta-opioid receptor antagonist naltrindole and the kappa-opioid receptor antagonist norbinaltorphimine, respectively, antagonized these effects. Application of the mu-opioid receptor agonist DAGO also resulted in an inhibition of acetylcholine release; however, both delta- and kappa-opioid receptor antagonists were able to block this effect. The mu-opioid receptor agonists morphine and (+)-nortilidine had no effect. These results indicate that acetylcholine release in human neocortex is inhibited through delta- and kappa-opioid receptors, but not through mu-opioid receptors. Acetylcholine release was significantly increased by the delta-opioid receptor antagonist naltrindole in the presence of a mixture of peptidase inhibitors providing evidence for a delta-opioid receptor-mediated inhibition of acetylcholine release by endogenous enkephalin. K(+)-evoked acetylcholine release in the presence of TTX was inhibited by U50488, but not by DPDPE, suggesting the presence of kappa-opioid receptors on cholinergic terminals and the localization of delta-receptors on cortical interneurons. Therefore, the potent effect of DPDPE on acetylcholine release is likely to be indirect, by modulation of intrinsic cortical neurons. These interneurons probably do not use GABA as neurotransmitter since both GABAA and GABAB receptor agonists (muscimol and baclofen, respectively) were without effect on acetylcholine release.

Opioid depression of respiration in neonatal rats.

1. The effects of opioid receptor agonists and antagonists on the breathing pattern of neonatal rats were studied. Three experimental approaches were taken. In the first approach, the effects of opioid agonists and antagonists on the spontaneous respiratory neural activity generated by brainstem-spinal cords isolated from neonatal rats aged 0-4 days postnatal (P0-4) maintained in vitro were studied. Secondly, similar studies were performed utilizing medullary slice preparations consisting of respiratory rhythm-generating regions (pre-Bötzinger complex). Thirdly, whole-body plethysmographic recordings were obtained from unanaesthetized neonatal (P0-18) rats before and after I.P. administration of opioid-receptor agonists and antagonists. 2. The mu-receptor agonists morphiceptin and DAGO (Tyr-D-Ala-Gly-[NMePhe]-Gly-ol), when added either to the solutions bathing the brainstems of neonatal rat brainstem-spinal cord preparations or bathing the medullary slice preparations, resulted in a naloxone-reversible, dose-dependent decrease in the frequency of respiratory rhythmic discharge. 3. The respiratory burst frequency and amplitude in vitro were unaffected by the addition of the delta-opioid receptor agonist DPDPE ([D-pen2,5]-enkephalin) and the kappa-opioid receptor agonist U50488 (trans-[+]-3,4-dichloro-N-methyl-N-(2-[1- pyrrolidinyl]cyclohexyl) benzene-acetamide) or the opioid receptor antagonist naloxone. 4. Intraperitoneal administration of the mu-opioid receptor agonist fentanyl resulted in a naloxone-reversible, dose-dependent decrease in the frequency and amplitude of breathing of unanaesthetized neonatal rats (P0-P10). I.P. administration of the delta-opioid receptor agonist DPDPE did not affect breathing of neonatal rats until the second week postnatally. 5. We conclude that opioids suppress the frequency of neonatal rat respiration by acting via mu-opioid receptors located within regions of the ventral medulla containing respiratory rhythm-generating centres (the pre-Bötzinger complex). delta-Opioid receptor activation does not affect breathing in neonatal rats until approximately the second week postnatally.

U-69593 prevents cocaine sensitization by normalizing basal accumbens dopamine.

Repeated intermittent administration of cocaine (20 mg kg-1, i.p.) for 3 days dramatically increased basal dopamine (DA) overflow in the nucleus accumbens (ACB) 48 h after the final daily injection. This cocaine pretreatment also produced a significant increase in stereotypy in response to a subsequent cocaine challenge. However, when the selective kappa-opioid receptor agonist U-69593 was administered in combination with cocaine for 3 days, these cocaine-induced biochemical and behavioral effects were abolished. It is suggested that the responsiveness of mesolimbic DA neurons to cocaine is intimately related to basal DA concentrations within the ACB and that U-69593, by normalizing cocaine-induced increases in basal DA overflow, may prevent the development of behavioral sensitization to cocaine.

Behavioral effects of systemically administered mu and kappa opioid agonists in the squirrel monkey: Peptides versus alkaloids

This study compared the effects of receptor-selective peptide and nonpeptide opioid agonists administered intramuscularly to squirrel monkeys responding under a fixed-interval 3-min schedule of stimulus termination. The mu opioid receptor agonist morphine (0.1–3.0 mg/kg) increased response rate at low doses and decreased it and quarter-life at higher doses. [ D-Ala 2,N-Me-Phe 4, Gly-ol]Enkephalin (DAMGO; 0.3–3.0 mg/kg) reduced quarter-life at the highest dose. The kappa opioid receptor agonist U50,488H (0.1–1.0 mg/kg) elevated response rate transiently and dose-dependently decreased quarter-life. Dynorphin (1–13) (0.3–10 mg/kg), a purported endogenous ligand of the kappa opioid receptor, decreased response rate slightly but significantly at 3.0 mg/kg and had no effect on quarter-life. Thus, the behavior of squirrel monkeys was affected by systematically administered peptide as well as by nonpeptide opioid drugs. The two alkaloids were much more effective than the two peptides, presumably because of greater ability to penetrate the blood-brain barrier. Quarter-life was often a more sensitive measure of drug effects than was response rate.

Kappa-Opioid receptors also increase potassium conductance.

Decrease of calcium conductance induced by opioid agonists has been reported by others for mu-, delta-, and kappa-opioid receptors. On the other hand, only mu- and delta-opioid receptors have been reported to increase potassium conductance. Intracellular recordings were made from guinea pig substantia gelatinosa neurons in a brain slice. A subset of cells (29 of 83) were hyperpolarized by the kappa-opioid receptor agonist U69593 with an EC50 of 23 nM. The kappa-opioid receptor antagonist norbinaltorphimine (10 nM) blocked the hyperpolarization by U69593 but had no effect on the mu-opioid hyperpolarization present in these cells. Naloxone (300 nM) shifted the U69593 dose-response curve to the right, giving an estimated Kd for naloxone of 7.5 and 8.1 nM measured in two cells. The hyperpolarization caused by U69593 was mediated by a potassium conductance as determined with voltage clamp experiments. This demonstrates, depending on the cell type, that all three major opioid receptors (mu, delta, and kappa) can increase potassium conductance as well as decrease calcium conductance.

The kappa-opioid receptor agonist U-69593 attenuates cocaine-induced behavioral sensitization in the rat

The effects of treatment with the selective kappa-opioid receptor agonist U-69593 upon cocaine-induced changes in locomotor activity and stereotypy were examined in rats. U-69593 (0.16 mg/kg s.c.) administered either acutely or chronically attenuated both the motor stimulant effect and stereotypy produced by an acute injection of cocaine (20 mg/kg i.p.). Daily cocaine treatment resulted in sensitization to both effects of cocaine. In contrast, no such sensitized responses were seen in animals which had received U-69593 either prior to or in conjunction with daily cocaine treatment. These data demonstrate that activation of kappa-opioid receptors attenuates the acute and chronic effects of cocaine on locomotor activity and stereotypy. Given the inhibitory effects ascribed to both exogenous and endogenous kappa-opioid agonists upon dopamine release in the mesolimbic dopaminergic system, it is suggested that this action may underlie the observed effects of U-69593 on cocaine-induced changes in locomotor activity and stereotypy.

Stimulus-evoked release of tritiated monoamines from rat periaqueductal gray slices in vitro and its receptor-mediated modulation

The periaqueductal gray is a brain region of considerable interest. It is innervated by monoamine-containing neurons as well as by a variety of peptidergic fiber systems, and it participates in the regulation of various functions. Virtually nothing is known about monoamine release in the periaqueductal gray and its receptor-mediated modulation. We therefore studied the release of radioactivity from periaqueductal gray slices preloaded with tritriated monoamines, using an in vitro superfusion method. The release of radioactivity from superfused periaqueductal gray slices after preloading of the tissue with [3H]noradrenaline increased upon electrical stimulation in a frequency-dependent manner. The stimulus-evoked release of radioactivity was Ca(2+)-dependent. Clonidine reduced and yohimbine enhanced the release. The inhibition curve for the effect of clonidine was shifted to the right in the presence of 10(-6) M yohimbine. While phenylephrine, isoprenaline, SK & F 38393, quinpirole, carbachol, [Arg8]vasopressin, alpha-MSH and ACTH-(1-24), at a concentration of 10(-6) M, did not influence the electrically evoked release of radioactivity, [Leu5]enkephalin reduced it. The selective mu-opioid receptor agonists [D-Ala2,NMePhe4,Gly-ol5]enkephalin and [D-Arg2,Lys4]-demorphin-(1----4)-amide reduced the release of radioactivity, whereas the selective delta opioid receptor agonist [D-Pen2,D-Pen5] enkephalin and the selective kappa opioid receptor agonist U-69593 had no effect. In the presence of naloxone, which by itself had no effect on the release of radioactivity, the effect of [D-Arg2,Lys4]dermorphin-(1-4)-amide was abolished. These results show that the release of noradrenaline from periaqueductal gray slices is via a Ca(2+)-dependent exocytotic process, and that it is modulated through alpha 2-adrenoceptors as well as via mu-opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Mu-opioid component of the ethylketocyclazocine (EKC) discriminative stimulus in the rat

The opioid receptor selectivity of the EKC discriminative stimulus was characterized in Fischer rats trained to discriminate 0.3 mg/kg EKC (SC) from saline in a two-choice discrete-trial avoidance paradigm. The putative kappa-opioid receptor agonists EKC and U50,488H completely generalized with the EKC cue at doses of 0.3 and 10 mg/kg, respectively. The putative mu-opioid receptor agonists morphine (M) and fentanyl also dose-dependently generalized with the EKC stimulus. The generalization of M with EKC was not symmetrical, EKC and U50,488H produced little or no M-appropriate responding in rats trained to discriminate 3.0 mg/kg M (SC) from saline. This generalization pattern may reflect a lack of opioid receptor selectivity of the EKC stimulus. However, distinct mu-opioid and kappa-opioid components of the EKC cue could be identified using graded doses of naloxone in EKC-trained rats. The discriminative effects of morphine and fentanyl were blocked completely by doses of 0.1-1.0 mg/kg naloxone, whereas doses of naloxone 3-10 times greater were necessary to block the discriminative effects of EKC and U50,488H. These results suggest that EKC produces a complex discriminative stimulus with mu-opioid and kappa-opioid components that can be separated using antagonists such as naloxone.