PubMed · 1749548
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M B Dolan. 1991. Pain control a top priority.. https://doi.org/10.1097/00152193-199112000-00002
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In vivo and in vitro binding studies with natural thebaine and its enantiomer, (+)-thebaine were conducted to elucidate further their interactions with the opioid system. (-)-Thebaine a key intermediate in the biosynthesis of morphine in the poppy plant (Papaver somniferum) and in mammalian tissue, was poorly effective antinociceptively in mice at doses to 30 mg/kg. Its principal behavioral manifestation was lethal convulsions. Naltrindole, at doses of 1 and 10 mg/kg did not block either the convulsions or lethal effects, suggesting that the delta-opioid receptor system was not involved in this action. Surprisingly, the dextrorotatory isomer exhibited significant antinociceptive activity in the tail-flick [ED50 = 8.9 (3.4-22.1) mg/kg], hot-plate [ED50 = 22.9 (10.9-48.1) mg/kg] and phenylquinone [ED50) = 1.9 (1.6-9.5) mg/kg] assays. Studies with opioid receptor-subtype antagonists, beta-funaltrexamine, nor-binaltorphimine and naltrindole, indicated that antinociception was associated with mu- and delta-opioid receptors. Results of displacement experiments supported the in vivo data. Significant competition for [3H]diprenorphine binding with both isomers for cloned mu- and delta-opioid receptors was observed. However, (-)-thebaine was more effective at the delta-opioid receptor (Ki = 1.02+/-0.01 microM) whereas (+)-thebaine was more effective at the mu-opioid receptor ( Ki = 2.75+/-0.01 microM). Opioid-induced antinociception associated with unnatural thebaine raises the possibility of additional mu- and delta-opioid receptor sites.
The pharmacological profile of a novel and newly discovered non-steroidal anti-inflammatory and analgesic compound, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyraz ole (FR140423), was investigated. In recombinant human cyclooxygenase enzyme assays, the inhibition of prostaglandin E2 formation by FR140423 was 150 times more selective for cyclooxygenase-2 than cyclooxygenase-1. Oral administration of FR140423 dose dependently reduced carrageenin-induced paw edema and adjuvant arthritis. These effects were two- to three-fold more potent than those of indomethacin. Unlike indomethacin, FR140423 did not induce mucosal lesions in the stomach. FR140423 showed dose-dependent anti-hyperalgesic effects in the yeast-induced hyperalgesic model. This effect was five-fold more potent than that of indomethacin. Furthermore, FR140423 increased the pain threshold in non-inflamed paws and, unlike indomethacin, it produced an analgesic effect in the tail-flick test. These analgesic effects were blocked by the mu-opioid antagonist naloxone. These results suggest that FR140423, a selective cyclooxygenase-2 inhibitor, is a potent non-steroidal anti-inflammatory drug (NSAID) without gastrointestinal side effects and is a unique compound having morphine-like analgesic effects.
The piglet displays similar postnatal development in respiration and sleep-wake behavior to the human. To shed light on the possible influence of opioid systems on these functions, this study assessed the density of mu- and delta-opioid receptors in brainstems of 2-3 and 5-7 (young), 14-17 (intermediate) and 20-21 (older) day-old piglets, using quantitative autoradiography. Serial 10 microns sections from fresh-frozen brains were incubated with either mu-(125I-DAGO) or delta-(125I-DPDPE) opioid ligands. The binding characteristics of each receptor remained unchanged over the age-range studied. delta-opioid receptor density was minimal in the young piglets, and increased over the age-range studied in all brainstem regions. mu-opioid receptor density exceeded delta-opioid density in all brainstem regions in young and older piglets, and remained unchanged with age. We conclude that, as in other species, the development of delta-opioid receptors in swine lags behind that of mu-opioid receptors, and that the distribution of each in the piglet's brainstem is distinct. The present findings help explain the changing influence of the mu- and delta-opioid systems on breating and state during postnatal development.