Effects of caffeine and 8-phenyltheophylline on the actions of purines and opiates in the guinea-pig ileum.

The antagonist effects of 8-phenyltheophylline (8-PT) and caffeine against the actions of adenosine, (-)-N6-(R-phenyl-isopropyl)-adenosine (PIA), morphine and nalorphine on the guinea pig ileum preparation were examined. Antagonism of both adenosine and PIA by caffeine and 8-PT was concentration dependent. The slopes of Schild plots for both alkylxanthines vs. adenosine were significantly less than -1 unless the adenosine reuptake blocker dipyridamole (0.1 microM) was include in the tissue bath. Under these conditions, the 95% confidence intervals of the Schild plot slopes embraced theoretical unity, suggesting competitive antagonism. The antagonism of PIA by the alkylxanthine was also competitive. Dipyridamole had no effect on the potency of PIA. The pA2 value for caffeine-adenosine was not different from that for caffeine-PIA, and the pA2 values of 8-PT-adenosine and 8-PT-PIA were similar, suggesting that these two agonists interacted with similar receptors. The pA2 values using 8-PT were approximately 1.5-fold higher than those employing caffeine, suggesting higher affinity for 8-PT at these receptors. Caffeine significantly antagonized morphine at all concentrations used (0.5-1.0 mM), but only antagonized nalorphine at the two highest concentrations. After treating ilea with the mu-specific irreversible antagonist beta-FNA (beta-funaltrexamine) (resulting in a preparation with relatively pure kappa receptor population), the antagonist effect of caffeine against morphine was reduced such that only a concentration of 1 mM resulted in significant antagonism, while the effects of caffeine against nalorphine were unchanged. 8-PT did not antagonize morphine or nalorphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Intrinsic activity and effects of guanyl-5'-yl imidodiphosphate, Gpp(NH)p and sodium ion on the affinity of dynorphin 1-13, nalorphine and nalorphine-7,8-oxide to kappa-opioid receptor.

Nalorphine and nalorphine-7,8-oxide (nalorphine epoxide) behaved as partial agonists on the kappa-receptor in the electrically stimulated mouse vas deferens. The effects of a GTP-analogue, GppNHp and Na+ on the inhibition of [3H]ethylketocyclazocine binding by dynorphin 1-13, nalorphine, its epoxide and naloxone (antagonist) were studied with a synaptosomal fraction of guinea pig brain (except a cerebellum) and compared with the intrinsic activity of the test drugs, which was estimated in the electrically stimulated mouse vas deferens. The effects of GppNHp and Na+ on the affinity of the drugs to the kappa-receptor correlated with their intrinsic activities.

Antagonism of the discriminative effects of ethylketazocine, cyclazocine, and nalorphine in macaques.

dl-Ethylketazocine (EKC, 0.01 mg/kg) and saline were established as discriminative stimuli for food-maintained responding in macaque monkeys. Thirty consecutive presses on a right or left lever were reinforced with food, contingent on whether EKC or saline were administered before the session. For tests of antagonism, naltrexone, or UM 979 [(l)-5,9-alpha-dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan] was administered concomitantly with EKC, dl-cyclazocine, or nalorphine. Both antagonists blocked completely the EKC discriminative stimulus. The antagonism of the stimulus and rate-altering effects of EKC was surmountable, with considerable intersubject variability in the magnitude of the EKC dose increase required to overcome the blockade. Cyclazocine and nalorphine, mixed agonist-antagonist opioids that share stimulus properties with EKC, were also susceptible to antagonism. Naltrexone antagonized completely the EKC stimulus effects of nalorphine; naltrexone and UM 979 antagonized completely the EKC stimulus effects of cyclazocine. Naltrexone antagonism of the cyclazocine stimulus was not surmountable, due to a lack of antagonism of the rate-decreasing effects of high cyclazocine doses.

Discriminative stimulus properties of nalorphine in the rhesus monkeys.

The discriminative stimulus properties of nalorphine were studied in rhesus monkeys trained to discriminate i.m. injections of nalorphine (1 mg/kg) from saline. During training, a two-lever paradigm was employed where a single, 3-min extinction schedule was followed by fixed-ratio-20 schedules of food presentation. During the fixed-rate schedules, responses on one of the two levers produced food when nalorphine had been administered and responses on the other lever produced food when saline had been administered. During stimulus generalization tests, responses on either lever produced food under the fixed-ratio schedule. The discriminative stimulus effects of nalorphine were antagonized by naloxone which, by itself, did not generalize to nalorphine. The kappa opiate agonists, ethylketocyclazocine, U-50,488, bremazocine, tifluadom, as well as two mixed kappa-sigma agonists, dl-cyclazocine and dl-N-allylnormetazocine (SKF-10047), generalized to nalorphine with the following potency ranking order: bremazocine greater than ethylketocyclazocine greater than tifluadom greater than cyclazocine greater than U-50,488 greater than N-allylnormetazocine greater than nalorphine. The levo-isomers of cyclazocine, N-allylnormetazocine or U-50,488 generalized to nalorphine whereas the dextroisomers did not. Generalization to nalorphine did not occur with the mu opiate agonists, morphine, methadone and meperidine, or the nonopiate compounds, phencyclidine, ketamine and chlorpromazine. The results suggest that a kappa opiate receptor mechanism mediates the discriminative effects of nalorphine in the rhesus monkey, which may also be involved with the naloxone-sensitive, sedative and dysphoric effects of nalorphine in humans.

Comparative effects of morphine and nalorphine on colonic motility in the conscious dog.

The effects of increased doses (0.05-02 mg/kg) of morphine and nalorphine on colonic motility were investigated in 15-22 h fasted dogs fitted with two strain gauge transducers on the transverse colon at 8 and 15 cm from the ileo-colonic junction. These effects were compared to those obtained after previous administration of naloxone (0.3 mg/kg), atropine (0.1 mg/kg) and methysergide (0.1 mg/kg). Both morphine and nalorphine, at a dose of 0.1 mg/kg increased the colonic motility index by 285 and 248% from 0 to 60 min respectively after their administration, these effects lasting 3.2 and 2.6 h. These stimulatory effects were abolished by previous administration of naloxone (0.3 mg/kg) or atropine (0.1 mg/kg) and limited to 60 min after methysergide (0.1 mg/kg). It was concluded that nalorphine may be considered as a potent morphinomimetic substance upon colonic motility and that cholinergic and serotonergic receptors were involved in the colonic response to morphine.

Effect of apomorphine on the antinociceptive activity of morphine.

Apomorphine pretreatment potentiated the analgesic effect of morphine in a dose-dependent manner both in rats and in mice measured by five different tests (writhing, hot plate, inflamed foot, tail-pinch and tail-flick procedures). Furthermore, apomorphine augmented the antinociceptive activity of morphine in tolerant animals as well. In morphine dependent mice the nalorphine precipitated jumping--a withdrawal symptom--was found inhibited by apomorphine treatment. The results are discussed in the light of the numerous but contradictory data available in the literature.

Acute opium poisoning: a report of two hundred cases in Iran.

The diagnosis and management of 200 cases of self-poisoning due to orally ingested crude opium in Iran is reported and discussed. Gastric lavage supported when necessary by nalorphine was effective treatment in the majority of cases because of the slow absorption of opium. Mechanical ventilation was required in twelve cases (6%) only. There were three deaths; two of these were due to pulmonary oedema which was apparently not the result of hypoxia.