benzofurans and naltrindole

The effects of a daily injection of the delta selective opioid antagonist naltrindole (1 mg/kg), from birth to postnatal day 19, on antinociceptive and behavioral responses to the mu selective agonist alfentanil (65 microg/kg) and the kappa selective agonist CI-977 (50 microg/kg) in 20-day-old male rats were investigated. Antinociception was assessed using the tail immersion test and behavioral testing was performed by employing an open field. The functional blockade of the delta receptor by naltrindole blocked the antinociceptive response to alfentanil but did not affect the antinociception induced by CI-977. The effects of alfentanil (increased exploration) and CI-977 (a marked hypoactivity) in the open field were not modified by neonatal naltrindole treatment. The results suggest a functional interaction between delta and mu receptors in the postnatal period but not between delta and kappa receptors. The data also suggest differences in the delta and mu receptors interacting in the modulation of antinociception and those involved in behavioral responses in the open field.

Topics: Alfentanil; Animals; Animals, Newborn; Benzofurans; Male; Naltrexone; Narcotic Antagonists; Narcotics; Pain Measurement; Psychomotor Performance; Pyrrolidines; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

In mammals, opioids act by interactions with three distinct types of receptors: mu, delta, or kappa opioid receptors. Using a novel assay of antinociception in the Northern grass frog, Rana pipiens, previous work demonstrated that selective mu, delta, or kappa opioids produced a potent antinociception when administered by the spinal route. The relative potency of this effect was highly correlated to that found in mammals. Present studies employing selective opioid antagonists, beta-FNA, NTI, or nor-BNI demonstrated that, in general, these antagonists were not selective in the amphibian model. These data have implications for the functional evolution of opioid receptors in vertebrates and suggest that the tested mu, delta, and kappa opioids mediate antinociception via a single type of opioid receptor in amphibians, termed the unireceptor.

Topics: Acetic Acid; Analgesics; Animals; Benzofurans; Female; Injections, Spinal; Male; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain Measurement; Pyrrolidines; Rana pipiens; Receptors, Opioid; Time Factors

Highly selective heterocyclic opioid ligands with potent delta-antagonist activity have been developed on the basis of the "message-address" concept. Using this strategy, benzofuran derivatives corresponding to the non-selective opioid antagonist, naloxone, and to the mu-opioid receptor selective agonists, oxymorphone and oxycodone, were synthesized. In vitro opioid receptor binding profiles and agonist/antagonist character of these compounds were determined in rat brain membrane preparations with highly selective radioligands. All three benzofuran derivatives displayed high affinities for the delta-opioid receptor, much less potency toward the mu-binding site, and were the least effective at the kappa-site. The results indicated that the addition of the bezofuran moiety to these fused ring opioids confers delta-receptor selectivity. The Na+ indices suggested a partial agonist character for oxymorphone- and oxycodone-benzofuran, and an antagonist character for naloxone-benzofuran. These compounds were capable of irreversible inhibition of opioid binding sites in a dose-dependent.

Topics: Animals; Benzeneacetamides; Benzofurans; Binding, Competitive; Brain; Cell Membrane; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Naloxone; Naltrexone; Oligopeptides; Oxycodone; Oxymorphone; Pyrrolidines; Radioligand Assay; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, mu; Tritium