Loss of antinociceptive efficacy in rat pups infused with morphine from osmotic minipumps.

We determined the susceptibility of two ages of rat pups to become tolerant to and dependent on morphine infusions from osmotic minipumps. Neonatal rats (postnatal day 6; P6) were infused for 72 h with morphine at 0.175 or 0.7 mg/kg/h. On P9, morphine's antinociceptive efficacy was reduced in both groups. P14 infant rats were also infused at 0.7 mg/kg/h. Unlike P9 neonates, morphine's potency was reduced in P17 infant rats, without a loss in efficacy. Yet raising the infusion rate to 1.1 mg/kg/h reduced morphine's efficacy. (3)H-DAMGO D-Ala2, N-MePhe4, Gly5-ol-enkephalin) binding revealed no change in the affinity or density of mu-opioid receptors at any age or in any treatment group. P9 and P17 pups were physically dependent on each infusion dose. Thus, chronic infusion of morphine affected both ages to such an extent that acutely administered morphine doses of even 1,000 mg/kg failed to restore antinociception. However, this effect cannot be attributed to changes in mu-opioid receptor number or affinity.

Embryo-fetal developmental and reproductive toxicology of vinyl chloride in rats.

Vinyl chloride (VC) exposure is primarily via inhalation in the workplace. The primary target organ of VC toxicity is the liver and occupational exposure to VC leads to hepatic angiosarcoma. However, based on epidemiological studies, researchers have been unable to ascertain the effect of occupational VC exposure on embryo-fetal development or reproductive function. A limited number of animal studies available in the literature have examined the effect of VC on embryo-fetal development, however, there are no published studies on the effect of VC exposure on reproductive capability. The current study was designed to assess the potential maternal and/or embryo-fetal developmental and 2-generation reproductive toxicity of inhaled VC in CD(R) Sprague-Dawley rats at exposure levels of 0, 10, 100, and 1100 ppm. In the embryo-fetal/developmental toxicity study, the female rats were exposed to VC daily from gestation day (GD) 6 through 19. In the reproductive toxicity study, the F(0) generation male and female rats were exposed to VC for a 10-week premating and 3-week mating periods. The F(0) generation male rats were exposed to VC until terminal euthanasia. The F(0) generation female rats were exposed from GD 0 through GD 20 and lactation day (LD) 4 through LD 25. Our results indicate that up to 1100 ppm VC exposure did not adversely affect embryo-fetal developmental or reproductive capability over 2 generations in rats. The primary target organ of VC, the liver, was affected as evidenced by an increase in liver weight and/or histologically identified cellular alterations, such as centrilobular hypertrophy at 100 and 1000 ppm. Based on the results of these studies, the no observed adverse effect level (NOAEL) for embryo-fetal/development is 1100 ppm, and the NOAEL for reproduction is 1100 ppm. The results from the current studies, which are a more comprehensive embryo-fetal/developmental and reproduction study, may be incorporated into future risk assessments of occupational exposure to VC where concerns regarding the effects of VC exposure remain.