PubMed · 10924423
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D Bevan, A Streetly, K Maxwell. 2000. Blaming the commentator.. https://doi.org/10.1136/ewjm.173.2.87-a
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We have presented a simple and sensitive method for determining pethidine, a narcotic analgesic drug in body fluids by gas chromatography-tandem mass spectrometry (GC-MS/MS). Pethidine and 4'-piperidinoacetophenone (internal standard) were extracted from body fluids with Bond Elut C(18) columns; the recoveries were above 85% for both compounds. The calibration curves for blood and urine showed good linearities in the range of 1.25-40 ng/ml. Its detection limits (signal-to-noise ratio=3) were estimated to be approximately 0.5 ng/ml of whole blood and urine.
Naloxone administration in the opioid dependent rat is associated with spinal glutamate release and NMDA receptor activation which reportedly is also responsible for opioid tolerance. We hypothesized that episodic withdrawal during chronic infusion of spinal morphine might paradoxically enhance tolerance. Rats (24/group) infused with intrathecal morphine (M) for 4 days (20 nmol/microl per h) were given a daily subcutaneous (s.c.) injection of naloxone 0.6 mg/kg per 0.2 ml (MN) or saline 0.2 ml (MS). A third saline infused group was given daily s.c. saline 0.2 ml (SS). Latencies (rear paw hot box) were tested immediately prior to each daily injection. After termination of each infusion, the dose effect of spinal morphine (0.1, 1, 10, and 100 nmol) was examined. The MN group showed a significantly greater decline in daily latencies compared with the MS group, but also had greater withdrawal hyperalgesia upon termination of the infusion. Dose response to spinal morphine was not significantly different in either MS or MN groups. Periodic abstinence thus enhanced nociception without significantly altering the antinociceptive effect of spinal morphine in this group.
The 17-amino acid neuropeptide nociceptin/Orphanin FQ (N/OFQ) was recently identified as the endogenous ligand for the opioid receptor-like (ORL1) receptor, a fourth member of the classical mu, delta, and kappa opioid receptor family. Although ORL1 clearly belongs to the opioid receptor family, it does not bind classical opiates and the ORL1-N/OFQ system has pharmacological actions distinct from the opioid receptor system. This new ligand-receptor system has generated active interest in the opioid community because of its wide distribution and involvement in a myriad of neurological pathways. The past two years have witnessed tremendous advances in the design and discovery of very potent and selective peptide and nonpeptide agonist and antagonist ligands at ORL1. These discoveries have facilitated the understanding of the role of the ORL1-N/OFQ system in a variety of processes such as pain modulation, anxiety, food intake, learning, memory, neurotransmitter release, reward pathways, and tolerance development. The ORL1 receptor therefore represents a new molecular target for the design of novel agents for anxiety, analgesia, and drug addiction. Indeed, there is tremendous interest in the pharmaceutical industry in the development of nonpeptide ligands such as the potent ORL1 agonist, Ro 64-6198, as anxiolytics and the ORL1 antagonist JTC-801 as novel analgesics. This review presents an overview of the various peptide and nonpeptide ORL1 ligands with an emphasis on their potential therapeutic utility in various human disorders.