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The Journal of Neuroscience, October 17, 2007, 27(42):11296-11305; doi:10.1523/JNEUROSCI.2586-07.2007

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Behavioral/Systems/Cognitive
Cyclooxygenase-1-Derived Prostaglandins in the Periaqueductal Gray Differentially Control C- versus A-Fiber-Evoked Spinal Nociception

J. Lianne Leith,¹ Alex W. Wilson,² Lucy F. Donaldson,¹ and Bridget M. Lumb¹

¹Department of Physiology, University of Bristol, Bristol BS8 1TD, United Kingdom, and ²Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex CM19 5AW, United Kingdom

Correspondence should be addressed to Dr. Lucy F. Donaldson, Department of Physiology, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK. Email: lucy.donaldson{at}bristol.ac.uk

Nonsteroidal anti-inflammatory drugs (NSAIDs) exert analgesic effects by inhibiting peripheral cyclooxygenases (COXs). It is now clear that these drugs also have central actions that include the modulation of descending control of spinal nociception from the midbrain periaqueductal gray (PAG). Descending control is a powerful determinant of the pain experience and is thus a potential target for analgesic drugs, including COX inhibitors. Noxious information from the periphery is conveyed to the spinal cord in A- and C-fiber nociceptors, which convey different qualities of the pain signal and have different roles in chronic pain. This in vivo study used different rates of skin heating to preferentially activate A- or C-heat nociceptors to further investigate the actions of COX inhibitors and prostaglandins in the PAG on spinal nociceptive processing. The results significantly advance our understanding of the central mechanisms underlying the actions of NSAIDs and prostaglandins by demonstrating that (1) in the PAG, it is COX-1 and not COX-2 that is responsible for acute antinociceptive effects of NSAIDs in vivo; (2) these effects are only evoked from the opioid-sensitive ventrolateral PAG; and (3) prostaglandins in the PAG exert tonic facilitatory control that targets C- rather than A-fiber-mediated spinal nociception. This selectivity of control is of particular significance given the distinct roles of A- and C-nociceptors in acute and chronic pain. Thus, effects of centrally acting prostaglandins are pivotal, we suggest, to both the understanding of nociceptive processing and the development of new analgesic drugs.

Key words: nociception; periaqueductal gray; descending control; prostaglandin; cyclooxygenase; C-nociceptor

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Received Jan. 18, 2007; revised Aug. 23, 2007; accepted Aug. 28, 2007.

Correspondence should be addressed to Dr. Lucy F. Donaldson, Department of Physiology, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK. Email: lucy.donaldson{at}bristol.ac.uk

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