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The presence of binding sites for ligands of mu and delta, in addition to kappa selectivity, have been demonstrated in the lumbo-sacral spinal cord of the rat by direct binding of [3H]ligands. These findings have been confirmed by competition studies. This information helps explain the observed pharmacology of opioids after intrathecal administration.
Attempts have been made to confirm reports that naloxonazine and Mr2034 are able to selectively antagonise morphine-induced analgesia and respiratory depression respectively. In the present studies these antagonists proved to be equi-effective against both the analgesic and respiratory depressant effects of morphine, suggesting that these two actions are mediated by a common receptor.
The selectivity and relative potencies of opiate receptor antagonists were compared on the mouse vas deferens preparation. ICI-174864 was found to be a highly selective antagonist at delta opiate receptors equal in potency to naltrexone in blocking the actions of delta agonists. Although less potent than naltrexone, beta-funaltrexamine (beta-FNA) and Mr-1452, like naltrexone, were less selective in that they blocked the actions of mu, delta and kappa agonists. The relative potencies of beta-FNA and Mr-1452 in antagonizing the three types of agonists also were similar to naltrexone.
Solubilization of opioid binding sites from guinea pig cerebellum by digitonin, in the absence and presence of NaCl, resulted in very similar yields (25-30%) of [3H]bremazocine binding. Saturation curves of [3H]bremazocine binding give linear Scatchard plots for both soluble and membrane-bound binding sites yielding similar Kd's and Bmax's. Soluble kappa sites seem to resemble closely their membrane-bound counterparts and retain high affinity and selectivity for various kappa opioid ligands. The apparent molecular weight of soluble kappa sites is ca. 4 X 10(5). Results from this study, along with our previous findings with toad and guinea pig brain, indicate that kappa sites (unlike mu and delta) can be solubilized in good yield by digitonin even in the absence of NaCl. This supports the hypothesis that kappa sites may represent molecular species different from those of mu and delta sites.
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A highly palatable diet (cafeteria diet) provokes an hyperphagia. The effects of Mu and Kappa opiate antagonists (Mu : Naltrexone 0.5 mg/Kg IP; Kappa Mr2266 0.5; 2.5; 10) and agonists (Mu Morphine 0.05; 0.1; 0.5; 2.5; Kappa Mr2033 0.5; 2.5) were studied on the nocturnal food intake of cafeteria rats and chow rats fed with monotonous food. At low doses Mu as well as Kappa antagonists do not modify the food intake of chow rats, but suppress the hyperphagia induced by the cafeteria diet. Kappa agonist provokes a decrease in food intake in chow and cafeteria rats while the Mu agonist at low doses suppresses the hyperphagia induced by cafeteria diet. The involvement of these two opioid systems in this type of hyperphagia is discussed.
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The effects of naloxone hydrochloride (NAL) and other opiate antagonists on blood-ethanol concentration (BEC) in acutely-ethanol-intoxicated rats were examined. Using a 1 mg/kg body wt. dose of NAL, the maximum decrease in BEC was found to occur at 30 min. At 30 min after administration of various doses of NAL, it was found that BEC was decreased maximally by a 2 mg/kg dose, whereas the first significant decrease was caused by a 10 micrograms/kg dose. BEC was also decreased by naltrexone (1 mg/kg), but not by a 4 mg/kg dose of any of four Mr compounds (Mr 1452, Mr 1453, Mr 2266 and Mr 2267). It is suggested that pharmacokinetic antagonism of acute alcohol intoxication by naloxone and naltrexone is unrelated to the property of opiate antagonism, but may involve the ability of certain such antagonists to interact with hepatic NAD+-dependent oxidative metabolism.
Male and female rats of the three Roman strains (Roman High-, Roman Low-, and Roman Control Avoidance; RHA, RLA and RCA, respectively) were familiarized with a highly palatable sweetened milk in a daily 30 min test. The animals were never food- or water-deprived prior to the test. Daily milk intake stabilised at a high level before drug tests were initiated. Effects of naloxone, diprenorphine, WIN 44,441-3, MR2266, MR2267, and ICI 154129 on milk consumption were investigated. Naloxone, diprenorphine and MR2266 each had comparable anorectic effects across strains and sexes. WIN 44,441-3 was relatively ineffective; MR2267 and ICI 154129 were without effect on milk consumption.
The goal of this study was to determine optimal conditions with which to measure opiate kappa binding sites in rat brain. Membranes were pretreated with mu-selective (BIT) and delta-selective (FIT) site-directed acylating agents (Rice et al., Science 220, 314-316), and the binding of [3H]bremazocine to the residual binding sites was defined as the kappa binding site. The binding of [3H]bremazocine to BIT/FIT-treated membranes was greatly increased by conducting the assay at 0 degrees C in the presence of 0.4 M NaCl. Using this 0 degrees C/NaCl assay condition, the binding of [3H]bremazocine was best described by a one-site binding model with a KD of 0.45 nM and a Bmax of 378 fmol/mg protein. Autoradiographic studies demonstrated that, using this assay condition, [3H]bremazocine densely labeled the deep layers of guinea pig cortex, an area known to be enriched with kappa binding sites. These and additional data suggest that the binding of [3H]bremazocine to the kappa binding site of rat brain is optimally assayed at 0 degrees C in the presence of 0.4 M NaCl using BIT/FIT-treated membranes and that rat brain is endowed with a high level of kappa binding sites.
Prodynorphin-derived peptides were tested for their effects on body temperature after intracerebroventricular administration to unrestrained male rats. Dynorphin A (Dyn A) (5 and 10 nmol) and Dynorphin A-(1-32) (Dyn A-(1-32) (2.5 and 5 nmol) lowered body temperature with a maximum approximately 30 min after administration. Dyn B (up to 50 nmol) did not induce hypothermia. Lower doses of all peptides did not alter body temperature. The hypothermic effect was significantly, but not completely prevented by MR1452 (30 nmol), a preferential antagonist of the kappa receptor, administered intracerebroventricularly. Naloxone, a mu receptor antagonist, naltrexone, its long acting analog up to doses of 100 nmol, as well as MR1453, the (+)-enantiomer of kappa antagonist MR1452 with no opioid binding properties, did not prevent the hypothermic effect. Moreover, episodic barrel rolling and bizarre postures elicited by Dyn A and Dyn A-(1-32) were reduced in rats pretreated i.c.v. with MR1452 (30 nmol), but not with naloxone (up to 100 nmol). Interestingly, des-Tyr-Dynorphin A (Dyn A-(2-17)), a fragment with virtually no opioid binding potential, was 4 times less potent that Dyn A in inducing hypothermia. These findings are consistent with the hypothesis that prodynorphin-derived peptides effects are not exclusively opioids in nature.
Intracellular microelectrodes were used to study the electrophysiological effects of U-50,488H on guinea-pig papillary muscle. U-50,488H (10(-5) M) caused a significant decrease in the maximum rate of depolarization and a decrease in the action potential duration. At high concentration (5 x 10(-5) M) U-50,488H induced a significant decrease of resting potential, maximum rate of depolarization, action potential amplitude and the action potential duration. The administration of MR-2266 (5 x 10(-7) M) partially antagonized the cardiac electrophysiological effects of U-50,488H. These results suggest that the electrophysiological effects of U-50,488H may be partially due to an interaction with opioid receptors.
The present study examined the effects of morphine, DAMGO, DPDPE and U-50, 488H on auricular rate on isolated right atria of the rat. All the opioid agonists tested induced a decrease of auricular rate. The maximal effect obtained with U-50,488H (75 +/- 8.3%) was significantly (p < 0.001) higher than that obtained with morphine (12 +/- 2.7%), DAMGO (8 +/- 0.6%) or DPDPE (11 +/- 1.8%). The inhibitory effects of U-50,488H were not antagonized by the presence of naloxone (10(-7) or 5 x 10(-7) M) or MR-2266 (10(-7) or 5 x 10 (-7) M). Moreover, U-50,488H did not change the auricular chronotropism in the presence of atropine (5 x 10(-7) M). In this case the maximal inhibitory effect was 79 +/- 6.7%, similar to that obtained with the kappa-agonist alone (75 +/- 8.3%). Propranolol (10(-8) or 5 x 10(-8) M) modified the inhibitory effect of U-50,488H. The maximal effect obtained by the kappa-agonist in presence of propranolol was 100 +/- 0 significantly (p < 0.01) higher than that obtained with U-50,488H alone. These results demonstrated that the depressant action of U-50,488H was not blocked in the presence of opioid receptor antagonists and probably does not involve opioid receptors. Furthermore, propranolol caused a dose-dependent potentiation of the effects of the kappa-agonist supporting the conclusion that it is not mediated by opioid receptors.
To investigate the role of brain opioid receptors in immune reactions, quaternary naltrexone (QNtx), a nonselective opioid antagonist which does not cross the brain-blood barrier, was tested for its immunomodulatory activity and ability to antagonize immunological changes produced by centrally applied delta-receptor agonist methionine-enkephalin (Met-Enk) and kappa-opioid receptor agonist MR 2034. Plaque-forming cell (PFC) response served as an immunological model. For this purpose, different groups of Wistar rats were centrally (intracerebroventricularly, i.c.v.) and peripherally (intraperitoneally, i.p., or subcutaneously, s.c.) treated with different doses of Met-Enk. MR 2034 and QNtx. Centrally injected Met-Enk and MR 2034 induced a dose-dependent potentiation and suppression of PFC response, respectively. Small amounts of i.c.v. given QNtx produced a dose-dependent increase in the number of PFC, whereas peripherally administered antagonist potentiated immune response in a dose-independent manner. A dose of 10 micrograms/kg of QNtx given i.c.v. completely abolished the immunopotentiation by Met-Enk. However, a large dose of 5 mg/kg of QNtx given s.c., did not affect the Met-Enk-induced immunoenhancement. Immunosuppression produced by i.c.v. injected MR 2034 was totally abrogated by prior i.c.v. application of QNtx, but partially blocked by s.c. administration of the antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
It is well established that kappa-opioid receptor agonists exert antiinflammatory and antihyperalgesic effects during nonspecific inflammation as well as suppressive effects on the development of humoral and cell-mediated immune responses to foreign antigens. The aim of this study was to investigate the ability of the kappa-opioid receptor agonist MR 2034 to modulate adjuvant arthritis in the rat. In the first series of experiments, treatments of Wistar rats were performed using several routes of drug administration: intraperitoneal (ip), intracaudal (ic), intracerebroventricular (icv) and intraplantar (ipl). MR 2034 significantly suppressed joint swelling after ip and ic treatment, slightly reduced inflammation after ipl treatment, and did not produce any effect after icv treatment. In the second series of experiments, the suppressive effect of ip injected MR 2034 was investigated using Wistar, Dark August (DA) and Lewis rats. In Wistar rats, MR 2034 significantly decreased the incidence of adjuvant arthritis, and suppressed mean joint score and aggregate joint score. Similarly, in DA rats treated with MR 2034, mean arthritic score was significantly suppressed, but other clinical parameters were not affected. In Lewis rats, however, ip treatment with MR 2034 failed to produce any suppressive effect on joint disease and even potentiated the initial development of arthritis. These data suggest that immunosuppressive and antiinflammatory action of MR 2034 markedly depend on the route of drug administration and strain susceptibility to opioids.
Intra-spinal cord injection of colchicine (2.5-5 micrograms/rat) produced an inhibition of reflex micturition leading to voiding suppression, bladder hypertrophy and overflow incontinence. Intraperitoneal administration of bremazocine, a kappa-receptor agonist with antagonistic properties for mu- and delta-receptors minimized the colchicine induced effects. The selective kappa-receptors agonist, U-69593, had little effect, while eledoisin or naloxone administration worsened rather than counteracted urine retention.
The present study describes the characterization of an opioid binding site on membranes prepared from the R1.1 cell line, a murine thymoma. Specific (-)[3H]bremazocine binding was saturable, stereoselective, and limited to a single high affinity binding site with a Kd value of 15.2 +/- 1.6 pM and a Bmax value of 54.8 +/- 6.0 fmol/mg of protein. The kappa-selective alkaloids and dynorphin peptides inhibited (-)[3H]bremazocine binding with Ki values of less than 1 nM, in contrast to mu- and delta-selective ligands. The high affinity of this site for alpha-neo-endorphin and U50,488 suggests that this kappa opioid binding site resembles the kappa 1b subtype. NaCl, as well as other mono- and divalent cations, inhibited (-)[3H]bremazocine binding. In the presence of NaCl, the nucleotides GTP, GDP, and the nonhydrolyzable analog guanylyl-5'-imidodiphosphate (Gpp(NH)p) also decreased (-)[3H]bremazocine binding, suggesting that this kappa opioid binding site is coupled to a G-protein. In summary, R1.1 cells possess a single high affinity kappa opioid receptor that shares many properties with brain kappa 1b opioid receptors.
The selective kappa opioid receptor agonist MR 2034 exerted pronounced suppression of plaque-forming cell (PFC) response following intraperitoneal (i.p.) administration in the rat. Pretreatment with preferential kappa and mu opioid receptor antagonists MR 2266 and naloxone, respectively, revealed that this effect was mediated mainly by kappa, and to a low extent by mu opioid receptors. Intracerebroventricular (i.c.v.) administration of quaternary naltrexone (QNtx) moderately attenuated, whereas i.p. given QNtx completely prevented the suppressive effect of MR 2034, suggesting a peripheral mechanism of action, and only minor involvement of brain opioid receptors. MR 2034 markedly decreased the PFC response of spleen cells obtained from in vivo immunized rats, treated in vitro with the opiate. The immunosuppressive action of MR 2034 in vitro was completely and partially blocked by equimolar concentrations of MR 2266 and naloxone, respectively. Antagonists alone produced stimulation of PFC following i.p. administration in the rat, but did not affect PFC response upon in vitro treatment. These results suggest that peripheral kappa opioid receptors down-regulate primary humoral immune response in the rat, and that this effect may be produced by direct interference with plasma cell activity.