Effects of the opioid analgesic oxymorphone hydrochloride on reproductive function in male and female rats.

BACKGROUND: Endogenous opioids seem to regulate hypothalamic gonadotropin release in both males and females, as evidenced by the effects of opioid agonists and antagonists on LHRH release and reproductive hormone levels. The effects of long-term oral administration of opioid analgesics on reproductive function have not been well characterized. METHODS: The reproductive effects of oxymorphone, a potent opioid agonist, were investigated in male and female Crl:CD(SD) IGS BR rats at oral doses of 0, 5, 10, and 25 mg/kg/day (25 animals/sex/group). Males were treated for approximately 9 weeks (mated after 4 weeks of dosing). Females were treated for 14 days before mating, and through Gestation Day (GD) 7. Estrous cycling was evaluated during the premating period. On GD15, pregnancy status and the numbers of corpora lutea, implantation sites, live and dead embryos were determined. Epididymal and testicular sperm counts and epididymal sperm motility and morphology were evaluated in males. RESULTS: Two males given 25 mg/kg/day died. Behavioral changes and deficits in body weight gain occurred at all doses. There were no effects of oxymorphone on reproductive function or sperm parameters in males. The estrous cycle was prolonged in females given 25 mg/kg/day (mean of 5.3 vs. 4.3 days in controls). A small, but consistent decrease in the numbers of corpora lutea (with associated decreases in implantation sites and embryos) occurred in females given > or =10 mg/kg/day. There were no effects on mating or fertility in females. CONCLUSIONS: Oxymorphone seems to partially inhibit ovulation in female rats, with no significant effects on male reproductive outcome.

Oxymorphone hydrochloride, a potent opioid analgesic, is not carcinogenic in rats or mice.

Despite their long history of chronic use, little information is available regarding the carcinogenicity of opioid analgesics. Oxymorphone is a potent morphinan-type mu-opioid analgesic used for treatment of moderate-to-severe pain. Oxymorphone was tested for carcinogenicity in Crl:CD IGS BR rats and CD-1 mice. Oxymorphone hydrochloride was administered orally once daily for 2 years to rats at doses of 2.5, 5 and 10 mg/kg/day (males) and 5, 10 and 25 mg/kg/day (females), and mice at 10, 25, 75 and 150 mg/kg/day (65 animals per sex per group; 100 animals per sex in controls). In rats, survival was generally higher than controls in oxymorphone-treated groups, attributable to lower body weight gain. In mice, survival was generally higher than controls in females at all doses and males given < or = 25 mg/kg/day but lower in males given > or = 75 mg/kg/day due to a high incidence of obstructive uropathy. Opioid-related clinical signs and reduced body weight gain occurred in both species throughout the study. Nonneoplastic findings associated with oxymorphone pharmacology included ocular and pulmonary changes in rats considered secondary to inhibition of blinking and mydriasis, and antitussive activity, respectively, and urinary tract and renal findings in mice considered secondary to urinary retention. There was no target organ toxicity, and no increase in any neoplastic lesions attributed to oxymorphone. Plasma oxymorphone levels achieved in these studies exceeded those in patients taking high therapeutic doses of oxymorphone (Area under the curve [AUC(0-24 h)] values up to 5.6-fold and 64-fold in rats and mice, respectively). Oxymorphone is not considered to be carcinogenic in rats or mice under the conditions of these studies.

Naloxone exacerbates intestinal and systemic anaphylaxis in the rat.

Following sensitization to ovalbumin (OA), male Wistar rats were pretreated with naloxone (20 mg/kg i.p.) and subjected to antigen challenge (3 mg OA i.p.). Naloxone exacerbated both systemic and intestinal anaphylaxis when injected 10 and 90 min before the antigen challenge. This was evidenced by a more pronounced drop in rectal temperature, higher hematocrit values, and by an enhanced elevation of basal short-circuit current (an indication of the secretory tone of the small intestine studied in Ussing chambers). Pretreatment with an equipotent does of methylnaloxone (200 mg/kg i.p.), a peripherally acting opiate antagonist, exacerbated the indices of intestinal anaphylaxis but had no apparent effect on indices of systemic anaphylaxis. Thus, our data strongly suggest that in the rat, components of the systemic hypersensitivity reaction are mediated through central opioid receptors, whereas the changes in gut function characterizing intestinal anaphylaxis are mediated through peripheral opioid receptors.

Differentiation of multiple analgesic opiate receptors.

In order to analyse opiate receptors mediating anti-nociception, the activity pattern of different opiates was determined by using hot-plate (45 degrees C and 56 degrees C), tail-flick and algolytic tests on rats, and the acetic acid stretching test on mice, for evaluation of analgesic activity. Potentiation of barbiturate anaesthesia, measurement of pupillary diameter, and a modification of pentetrazol convulsion, were used for evaluation of non-analgesic activity. The efficacy and affinity constant (pA2) of the proposed opiate A receptor agonist and B receptor antagonist drug N-cyclopropylmethyl-norazido-dihydroisomorphine (CAM) were determined. CAM produced several opiate agonist (morphine-like) effects, often stronger than morphine, in three of the analgesic tests and two of the non-analgesic tests. On the other hand CAM proved to be a very strong narcotic antagonist, as potent as naloxone as evidenced by identical pA2 values, in the algolytic, 45 degrees C hot-plate and pentetrazol tests, but not in the 56 degrees C hot-plate, tail-flick and acetic acid tests. The potency differences for the actions of morphine and CAM in a heat test (56 degrees C hot-plate) compared with a non-heat test (acetic acid stretching) were found to be 8.6 and 540 respectively. It is concluded that opiate analgesia might be mediated by at least two receptors classified in terms of the antagonistic or agonistic activity of CAM.

The pharmacology of 14-hydroxyazidomorphine.

6-Deoxy-6-dihydroazido-14-hydroxyisomorphine (14-hydroxyazidomorphine) was synthesized, its analgesic potency in mice and rats, its antitussive effect in rats and its dependence liability in mice, rats and monkeys were studied. Azidomorphine the 14-nonhydroxylated parent molecule, morphine, hydromorphone and oxymorphone were used for comparison. 14-Hdroxyazidomorphine proved to be as potent an analgesic as azidomorphine, even more potent as an antitussive, and showed the same low tolerance and dependence capacity. It was 11-6 times less toxic than azidomorphine in mice and 6-5 times less toxic in rats.