PubMed · 6786621
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
P Kincaid-Smith. 1981-05-30. Analgesic nephropathy.. https://doi.org/10.1136/bmj.282.6278.1790
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
Many clinical case reports have suggested that sustained opioid exposure can elicit unexpected, paradoxical pain. Here, we explore the possibility that (1) opioid-induced pain results from tonic activation of descending pain facilitation arising in the rostral ventromedial medulla (RVM) and (2) the presence of such pain manifests behaviorally as antinociceptive tolerance. Rats implanted subcutaneously with pellets or osmotic minipumps delivering morphine displayed time-related tactile allodynia and thermal hyperalgesia (i. e., opioid-induced "pain"); placebo pellets or saline minipumps did not change thresholds. Opioid-induced pain was observed while morphine delivery continued and while the rats were not in withdrawal. RVM lidocaine, or bilateral lesions of the dorsolateral funiculus (DLF), did not change response thresholds in placebo-pelleted rats but blocked opioid-induced pain. The intrathecal morphine antinociceptive dose-response curve (DRC) in morphine-pelleted rats was displaced to the right of that in placebo-pelleted rats, indicating antinociceptive "tolerance." RVM lidocaine or bilateral DLF lesion did not alter the intrathecal morphine DRC in placebo-pelleted rats but blocked the rightward displacement seen in morphine-pelleted animals. The subcutaneous morphine antinociceptive DRC in morphine-pelleted rats was displaced to the right of that in placebo-pelleted rats; this right shift was blocked by RVM lidocaine. The data show that (1) opioids elicit pain through tonic activation of bulbospinal facilitation from the RVM, (2) increased pain decreases spinal opioid antinociceptive potency, and (3) blockade of pain restores antinociceptive potency, revealing no change in antinociceptive signal transduction. These studies offer a mechanism for paradoxical opioid-induced pain and allow the development of approaches by which the loss of analgesic activity of opioids might be inhibited.
The N-methyl-D-aspartate (NMDA) antagonist ifenprodil and several structurally related compounds are highly selective for the NR2B-containing receptor subtype. This selectivity could provide an explanation for the reported difference of the analgesic and side-effect profile of ifenprodil-like compounds from other NMDA antagonists. In this work, we have queried if the ifenprodil-induced antinociception can be attributed to the block of NMDA receptors in the spinal cord. Ifenprodil and some other NMDA antagonists (MK-801, memantine) were tested in a model of inflammatory pain (Randall-Selitto) in rats. The in vivo NMDA antagonism was assessed in anaesthetised rats on responses of spinal dorsal horn (DH) neurones to iontophoretic NMDA and in the model of single motor unit (SMU) wind-up. Ifenprodil, MK-801 and memantine dose-dependently increased nociceptive thresholds in the Randall-Selitto model. Antinociceptive doses of the channel blockers selectively antagonised NMDA responses of DH neurones and inhibited wind-up. In contrast, antinociceptive doses of ifenprodil did not show any NMDA antagonism in electrophysiological tests. Although ifenprodil did not inhibit the SMU responses to noxious stimuli in spinalised rats, it markedly and dose-dependently inhibited nociceptive SMU responses in sham-spinalised rats. These results argue against the spinal cord being the principal site of antinociceptive action of ifenprodil; supraspinal structures seem to be involved in this effect.
Ginsenosides (GS), an extract of Panax ginseng, have been reported to be effective in inducing vascular relaxation mediated by nitric oxide (NO) release. The present experiments were designed to determine whether this GS-induced vasorelaxation also involves Ca2+ -activated K+ (KCa) channels in vascular smooth muscle cells (VSMC) in addition to endothelium-derived NO. GS induced vasorelaxation in rat aortic rings, which had been precontracted with phenylephrine, in a concentration-dependent manner. This GS-induced relaxation was partially reversed by tetraethylammonium (TEA), an inhibitor of KCa channels; methylene blue (MB), an inhibitor of soluble guanylate cyclase; as well as Nomega-nitro-L-arginine (L-NNA), but not by glybenclamide. In cultured VSMC and endothelial cells, KCa channels were activated by GS. This action was abolished by TEA, but was not blocked by glybenclamide. In addition, the GS-induced activity of KCa channels was partially inhibited by MB or H-8. These results indicate that the activation of KCa channels involved, at least in part, the GS-induced vasorelaxation of rat aorta.