Analgesic profile of rimazolium as compared to different classes of pain killers.
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)
Furst
S
S
Department of Pharmacology, Semmelweis University of Medicine, Budapest, Hungary.
Gyires
K
K
Knoll
J
J
D000700:Analgesics / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001835:Body Weight / Q000187:drug effects; D002415:Cats; D004285:Dogs; D004361:Drug Tolerance; D006168:Guinea Pigs; D007213:Indomethacin / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D011744:Pyrimidinones / Q000494:pharmacology* / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D013276:Stomach Ulcer / Q000139:chemically induced; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D019966:Substance-Related Disorders / Q000523:psychology
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011744:Pyrimidinones; C100296:probon; D007213:Indomethacin