Dissociation of opioid antinociception and central gastrointestinal propulsion in the mouse: Studies with naloxonazine

The effect of pretreatment with naloxonazine on opioid-mediated antinociception against a thermal stimulus (55°C warm-water tail-flick test) and inhibition of gastrointestinal transit at supraspinal and spinal levels was studied in unanesthetized mice. The mu-selective agonist [D-Ala², N-methyl-Phe⁴, Gly⁵-ol]enkephalin (DAGO), the delta-selective agonist [D-Pen², D-Pen⁵]enkephalin (DPDPE) and the reference mu-acting agonist morphine, all produced antinociception after either i.c.v. or intrathecal(ly) (i.t.) administration. Morphine and DAGO, but not DPDPE, inhibited gastrointestinal transit after i.c.v. administration, whereas all three agonists slowed gut propulsion when given i.t. A single s.c. naloxonazine pretreatment, 35 mg/kg given 24 hr earlier, failed to displace the dose-response line for i.c.v. DPDPE antinociception but produced a marked rightward displacement of the i.c.v. morphine and DAGO dose-response lines for antinociception. In contrast, naloxonazine (35 mg/kg) pretreatment did not alter the antinociceptive effects of i.t. morphine, DAGO or DPDPE. The effects of naloxonazine pretreatment on inhibition of gut propulsion were the converse of those observed for antinociception at supraspinal and spinal sites; naloxonazine had no effect on the antitransit properties of i.c.v. morphine and DAGO but inhibited the antitransit properties of all three agonists when they were given i.t. These results support the view that opioids may produce their supraspinal antitransit effects at a receptor different from that mediating antinociception; morphine and DAGO mediate their antitransit effects at a naloxonazine-insensitive site, whereas their antinociceptive effects are produced at the naloxonazine-sensitive receptor. When given into the brain of mice, DPDPE appears to be producing its tail-flick antinociception at a different (non-mu) receptor, probably the delta receptor. Additionally, it appears that opioids produce their spinal inhibition of gastrointestinal transit at naloxonazine-sensitive sites, whereas spinal antinociception is insensitive to naloxonazine. These results demonstrate the difficulty in assigning specific effects to specific opioid receptors; differences are related to the endpoint studied as well as central nervous system site (brain and spinal cord).