EVIDENCE FOR AN ACTION OF MORPHINE AND THE ENKEPHALINS ON SENSORY NERVE ENDINGS IN THE MOUSE PERITONEUM

Abstract

1 A modification of the abdominal constriction test in mice has been developed, and used to study the antinociceptive effects of morphine and several related drugs. In most experiments, acetic acid (0.6% i.p.) was used as the nociceptive stimulus, and in a few cases, acetylcholine (3.2mg/kgi.p.) was used. When the abdominal constriction response had reached a maximum, the drugs under test were given intraperitoneally, and their ability to decrease the number of abdominal constrictions was determined, beginning immediately after its administration. The aim of this study was to investigate the possibility that morphine and its congeners may produce an antinociceptive effect by an action within the peritoneum. 2 It was found that morphine was an extremely potent antinociceptive agent in this modified test, with an ID₅₀ of 5.4 × 10⁻⁹ mol/kg (1.54 μg/kg). Codeine and pentazocine were about 40 times less active and oxymorphine was about twice as potent as morphine. Met- and Leu-enkephalin were also potent but their action diminished very rapidly with time. Ketocyclazocine was the most potent substance tested, and had an ID₅₀ value of 1.26 × 10¹⁰ mol/kg (0.036 μg/kg). All the drugs tested produced their maximal effect within 1 or 2 min of administration. 3 Pretreatment of the mice with naloxone caused a dose-dependent shift to the right of the dose-response curve to morphine. The pAx plot was linear over part of the range, with a slope of − 1.02 and the ‘apparent pA₂’ value was 6.14. Naloxone was much less effective in antagonizing Met-enkephalin, and caused a slight potentiation of ketocyclazocine and pentazocine and of cocaine, which was used for comparison. 4 Pretreatment of mice with morphine, 3 h earlier, caused a marked tolerance to a subsequent dose of morphine, and a potentiation of the antagonist potency of naloxone. However, there was little cross-tolerance between morphine and Leu-enkephalin. 5 It is concluded that morphine and its congeners can produce an antinociceptive effect by an action within the mouse peritoneum, presumably by interacting with one or more types of opioid receptors which may be situated on sensory nerve endings.