No abstract

Alcohol use in children and adolescents is widespread. However, very little is known about the effects of alcohol exposure during this period of postnatal development. The goal of the present study was to compare the relative sensitivity to the sedative effects of alcohol in periadolescent and adult rats. After treatment with either 4 or 5 g/kg ethanol, both 20- and 30-day-old rats regained their righting reflex significantly earlier than 60-day old rats. In 30-day-old rats, serum ethanol concentrations (SECs) were significantly greater at the time of the recovery of the righting reflex than 60-day-old rats. Developmental differences in the effects of ethanol on locomotor activity were also observed. In 60-day-old rats, 2.5 g/kg ethanol generally decreased locomotor activity. Ethanol did not significantly alter locomotor activity in 20- and 30-day-old rats. Finally there were significant developmental differences in the pharmacokinetics of ethanol with a significant delay in the time to peak SECs in 60-day-old rats relative to 20- and 30-day-old rats. These findings indicate that peri-adolescent rats are less sensitive to the sedative effects of ethanol as they recovered their righting reflex earlier and at significantly higher SECs than adult rats.

Opioid receptors in the gastrointestinal (GI) tract mediate the effects of endogenous opioid peptides and exogenously administered opioid analgesics, on a variety of physiological functions associated with motility, secretion and visceral pain. The studies reviewed or reported here describe a range of in vivo activities of opioid receptor antagonists upon GI function in rodents, focusing on mu receptors. Naloxone, and the peripherally acting mu-opioid receptor antagonists alvimopan and methylnaltrexone, reverse morphine-induced inhibition of GI transit in mice and rats, and morphine- or loperamide-induced inhibition of castor oil-induced diarrhoea in mice. At doses producing maximal reversal of morphine-induced effects upon GI transit, only the central nervous system (CNS) penetrant antagonist naloxone was able to reverse morphine-induced analgesia. Both central and peripheral opioid antagonists may affect GI function and/or visceromotor sensitivity in the absence of exogenous opioid analgesics, suggesting a constitutive role for endogenous opioid peptides in the control of GI physiology. Furthermore, in contrast to naloxone, alvimopan does not produce hypersensitivity to the visceromotor response induced by nociceptive levels of colorectal distension in a rodent model of post-inflammatory colonic hypersensitivity, suggesting that in the periphery endogenous mu-opioid receptor-mediated mechanisms do not regulate colonic sensitivity. The data support the hypothesis that peripherally acting opioid antagonists may be able to selectively block opioid receptors in the GI tract, thereby preserving normal GI physiology, while not blocking the effects of endogenous opioid peptides or exogenous opioid analgesics in the CNS. These findings suggest that the primary sites of action of mu-opioid agonists with respect to inhibition of GI function are in the periphery, whereas analgesic activity resides primarily in the CNS.

Selective delta opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable delta agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.