1,6-Dimethyl-3-carbethoxy-4-oxo-6,7,8,9-tetrahydro-homopyrimidazol (rimazolium, MZ-144) proved to be effective in all the
analgesic assays used (independently of the nociceptive stimulus applied) (hot plate, tail flick, writhing tests, Randall-Selitto test, tail
clip, surgical pain) differing in this respect from the nonsteroidal antiinflammatory analgetics. The
analgesic, antiinflammatory and gastrointestinal effects of
rimazolium,
morphine and
prostaglandin synthesis inhibitors were compared. The
prostaglandin (PG) mediated
pain (
acetylcholine-,
adenosine triphosphate- and
acetic acid-induced writhing) was inhibited by all the three types of compounds, however,
pain reaction where PGs are not involved (MgSO4-writhing) was inhibited only by
rimazolium and
morphine but not, or only slightly, by PG synthesis inhibitors. While the
analgesic effect of
rimazolium alone was not reversed by
naloxone, the full
analgesia evoked by the ineffective doses of
morphine and
rimazolium combinations was completely
naloxone reversible (pA2 = 8.6). In addition,
rimazolium produced weak
analgesia by intrathecal administration, and its concomitant s.c. administration enhanced the
analgesic effect of intrathecally administered
morphine. Furthermore, chronic treatment with
rimazolium failed to influence its
analgesic activity, and no tolerance developed and no
naloxone precipitated withdrawal syndrome could be seen. In addition,
rimazolium did not substitute for
morphine in
morphine dependent rats, after
morphine withdrawal, thus indicating that
rimazolium lacks the capacity of producing
opiate-like physiological dependence. Also
rimazolium fails to show any indication of
narcotic-like abuse liability by any of clinical assessments.
Rimazolium,
morphine and
indometacin inhibited the
carrageenin-induced
edema formation. Gastrointestinal lesions produced by
indometacin were depressed by
rimazolium and enhanced by
morphine.(ABSTRACT TRUNCATED AT 250 WORDS)