Abstract
1. The analgesic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is partly due to the fact that they act upon the periaqueductal gray matter (PAG) and the rostral ventromedial medulla of the brain stem and thus activate the descending pain-control system, which inhibits nociceptive transmission at the spinal dorsal horn.
2. The analgesic action of dipyrone (metamizol) and of lysine-acetylsalicylate (LASA), two well-known NSAIDs, whether microinjected into the PAG or given systemically, can be reverted by naloxone. Repeated administration of dipyrone or LASA induces tolerance to their antinociceptive effect, with cross-tolerance to morphine, and a withdrawal syndrome upon naloxone administration. Dipyrone tolerance can be reverted by proglumide, a cholecystokinin antagonist.
3. These findings reveal a close association between the central action of NSAIDs and endogenous opioids.
Keywords: NSAID, nonopioid analgesics, opioid analgesia, periaqueductal gray, rostral ventromedial medulla, cholecystokinin, descending pain control, opioid tolerance
REFERENCES
- Dickenson, A. H., Oliveras, J.-L., and Besson, J. M. (1979). Role of the nucleus raphe magnus in opiate analgesia as studied by the microinjection technique in the rat. Brain Res.170:95–111. [DOI] [PubMed] [Google Scholar]
- Fields, H. L., and Basbaum, A. I. (1999). Central nervous system mechanisms of pain modulation. InWall, P.D., and Melzack, R. (eds.), Textbook of Pain, 4th edn., Churchill Livingstone, London, pp. 309–329. [Google Scholar]
- Hernández, N., and Vanegas, H. (2000). Involvement of supraspinal and spinal endogenous opioids in the antinociceptive effect of intravenously injected dipyrone (DIP). Soc. Neurosci. Abstr.26:661. [Google Scholar]
- Hernandez, N., and Vanegas, H. (2001). Antinociception induced by PAG-microinjected dipyrone (metamizol) in rats: Involvement of spinal endogenous opioids. Brain Res.896:175–178. [DOI] [PubMed] [Google Scholar]
- Jones, S. L. (1996). Dipyrone into the nucleus raphe magnus inhibits the rat nociceptive tail-flick reflex. Eur. J. Pharmacol.318:37–40. [DOI] [PubMed] [Google Scholar]
- Pernia, A. J., Tortorici, V., and Vanegas, H. (2002). Antinociception and tolerance elicited by acetylsalicylate in the PAG depend on endogenous opioids. In Abstract of the 10th World Congress on Pain, San Diego, CA, p. 261.
- Pernia, A. J., Tortorici, V., and Vanegas, H. (unpublished). Antinociception and tolerance elicited by systemic acetylsalicylate depend on endogenous opioids.
- Tortorici, V., Morgan, M. M., and Vanegas, H. (2001). Tolerance to repeated microinjection of morphine into the periaqueductal gray is associated with changes in the behavior of off-and on-cells in the rostral ventromedial medulla. Pain89:237–244. [DOI] [PubMed] [Google Scholar]
- Tortorici,V., Robbins, C. S., and Morgan, M. M. (1999).Tolerance to the antinociceptive effect of morphine microinjections into the ventral but not lateral-dorsal periaqueductal gray of the rat. Behav. Neurosci.113:833–839. [DOI] [PubMed] [Google Scholar]
- Tortorici, V., Rodriguez, F., Nogueira, L., Aponte, Y., and Vanegas, H. (2000). Proglumide, a CCK antagonist, prevents and reverts tolerance to the antinociceptive effect of PAG-microinjected dipyrone in rats. Soc. Neurosci. Abstr.26:660. [Google Scholar]
- Tortorici, V., and Vanegas, H. (1994). Putative role of medullary off-and on-cells in the antinociception produced by dipyrone (metamizol) administered systemically or microinjected intoPAG.Pain57:197–205. [DOI] [PubMed] [Google Scholar]
- Tortorici, V., and Vanegas, H. (1995). Antinociception induced by systemic or PAG-microinjected lysineacetylsalicylate in rats. Effects on tail-flick related activity of medullary off-and on-cells. Eur. J. Neurosci.7:1857–1865. [DOI] [PubMed] [Google Scholar]
- Tortorici, V., and Vanegas, H. (2000). Opioid tolerance induced by metamizol (dipyrone) microinjections into the periaqueductal gray of rats. Eur. J. Neurosci.12:4074–4080. [DOI] [PubMed] [Google Scholar]
- Tortorici, V., Vasquez, E., and Vanegas, H. (1996). Naloxone partial reversal of the antinociception produced by dipyrone microinjected in the periaqueductal gray of rats. Possible involvement of medullary off-and on-cells. Brain Res.725:106–110. [DOI] [PubMed] [Google Scholar]
- Vanegas, H., Tortorici,V., Eblen-Zajjur, A., and Vasquez, E. (1997).PAG-microinjected dipyrone (metamizol) inhibits responses of spinal dorsal horn neurons to natural noxious stimulation in rats. Brain Res.759:171–174. [DOI] [PubMed] [Google Scholar]
- Vasquez, E., and Vanegas, H. (2000). The antinociceptive effect of PAG-microinjected dipyrone in rats is mediated by endogenous opioids of the rostral ventromedial medulla. Brain Res.854:249–252. [DOI] [PubMed] [Google Scholar]
- Vaughan, C. W., Ingram, S. L., Connor, M. A., and Christie, M. J. (1997). How opioids inhibit GABAmediated neurotransmission. Nature (Lond.)390:611–614. [DOI] [PubMed] [Google Scholar]
- Walker, J. S., (1995). NSAID: An update on their analgesic effects. Clin. Exp. Pharmacol. Physiol.22:855–860. [DOI] [PubMed] [Google Scholar]
- Walker, J. S., and Levy, G. (1990). Effect of multiple dosing on the analgesic action of diflunisal in rats. Life Sci.46: 737–742. [DOI] [PubMed] [Google Scholar]
- Watkins, L. R., Kinscheck, I. B., and Mayer, D. J. (1984). Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide. Science224:395–396. [DOI] [PubMed] [Google Scholar]
- Yaksh, T. L., Yeung, J. C., and Rudy, T.A. (1976). Systematic examination in the rat of brain sites sensitive to the direct application of morphine: Observation of differential effects within the periaqueductal gray. Brain Res.114:83–103. [DOI] [PubMed] [Google Scholar]