Associate editor: P.C. MolenaarCOX-dependent mechanisms involved in the antinociceptive action of NSAIDs at central and peripheral sites
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed and widely used drugs in the management of pain, especially pain associated with inflammatory conditions. Despite the wide use of NSAIDs during the last century (the first NSAID, aspirin, was developed in the late 1800s), for a long period only little was known about the mode of action of these drugs. It was not until the 1970s that investigations into the mode of action of aspirin-like drugs were taken over by prostaglandin researchers, who showed an association between prostaglandin production and the action of aspirin-like drugs (Vane, 1964). In 1971, Vane discovered that NSAIDs could inhibit prostaglandin synthesis and proposed that this mechanism was the basis of their pharmacological action (Vane, 1971). This hypothesis was supported by other experimental data demonstrating the presence of prostaglandins at sites of inflammation (Willis, 1969, Di Rosa et al., 1971) and their ability to reproduce some of the cardinal signs of inflammation (Arora et al., 1970). The biomolecular target of NSAIDs was not identified until 1976 when a purified and enzymatically active cyclooxygenase (COX) was isolated from sheep vesicular glands (Hemler & Lands, 1976). It took several years more i.e. until the late 1980s before it was discovered that COX exists in at least two isoforms (Kujubu et al., 1991, Hla & Neilson, 1992), COX-1 and COX-2, and that “classical” NSAIDs are non-selective inhibitors of both isozymes (Xie et al., 1992).
Initially, the principle mode of the antinociceptive action of NSAIDs was considered to be related to their anti-inflammatory action and was thought to be due solely to the inhibition of prostaglandin production at the site of inflammation. This argument has its origin in the experimental observations of Horton (1963), Willis (1969), Juhlin and Michaelsson (1969), Crunkhorn and Willis (1971), Karim (1971) and, particularly, those of Ferreira (1972). By estimating pain in healthy volunteers following the intradermal administration of various inflammatory mediators (histamine, bradykinin and alprosadil (PGE1)), Ferreira could show that whilst PGE2 ‘per se’ produced no pain, its presence was essential for the induction of pain by histamine and bradykinin. These findings form the basis of the currently accepted view that PGs are not generally algogenic but act as sensitizing agents for enhancing the nociceptive properties of various inflammatory mediators. Additional evidence for the concept that NSAIDs exert their anti-nociceptive action peripherally comes from tissue distribution data obtained from whole-body autoradiography after administration of various NSAIDs in rats (Brune, 1974). In particular, it was shown that NSAIDs, because of the acidic moiety, can be extensively accumulated in inflamed tissues, where they exert their pharmacological action. At that time, the distribution of NSAIDs in other tissues, in particular in the CNS, was construed only as an explanation for the organ specific toxicity and was not thought to be related to their antinociceptive action (Brune, 1974).
The traditional belief that NSAIDs have exclusively a peripheral mode of action was not challenged until the beginning of the 1990s in the wake of the growing evidence that the anti-inflammatory and the antinociceptive effects of NSAIDs are unrelated (McCormack & Brune, 1991). So, an existence of some central antinociceptive mechanisms, an idea initially put forward by Hazlick as early as 1926 (Jurna, 1997), has been suggested (Ferreira et al., 1978, Carlsson et al., 1988). Although various mechanisms have been proposed to account for central effects of NSAIDs (Bjorkman, 1995), inhibition of prostaglandin synthesis (Abdel-Halim et al., 1978, Ferreira et al., 1978) in the CNS, and particularly in the spinal cord (Jurna et al., 1992, Malmberg & Yaksh, 1992), appears to be a property of all NSAIDs. Furthermore, the finding that both COX isozymes, i.e. COX-1 and COX-2, are expressed in the CNS (Kaufmann et al., 1997) and the observation that experimental induction of peripheral inflammation is associated with an increase in the expression of COX-2 in the spinal cord (Beiche et al., 1996) have been used as evidence supporting a central antinociceptive mechanism of action of NSAIDs (Vasquez et al., 2001, Vanegas, 2002).
This review of the central and peripheral antinociceptive mechanisms of action of NSAIDs mainly focuses on the inhibition of cyclooxygenase-mediated prostaglandin synthesis, as a class-like pharmacological property of NSAIDs. Cyclooxygenase-independent actions of NSAIDs, including cellular mechanisms mediated via interference with transcription factors (Tegeder et al., 2001b) and direct modulation of the activities of various ion channels (Lee et al., 2003), have so far only been observed with a few NSAIDs and are therefore not discussed here in detail.
The mechanisms and clinical manifestations involved in inflammatory pain, a condition commonly treated with NSAIDs, are dealt with first and this is followed by a discussion on the location and regulation of the main target of NSAIDs, cyclooxygenases at the central and peripheral sites. Biochemical aspects of prostaglandin synthesis are presented and special attention is given to the mechanisms of the prostaglandin-mediated hyperalgesia. The final section deals with the antihyperalgesic action of NSAIDs where attention is given to the currently available experimental and clinical evidence supporting their peripheral and central mechanisms. The contribution of both mechanisms to the overall antinociceptive action of this class of analgesics is discussed.
Section snippets
Inflammatory pain
The nociceptive signalling in physiological pain is initiated by activation of the specialized pain receptors (nociceptors), which are polymodal sensory fibres of the primary sensory neurons located in trigeminal and dorsal root ganglia (DRG). Although the nociceptors are able to respond to a wide range of stimulus modalities, different noxious stimuli generally cause activation of a single receptor [e.g. heat activates TRPV1-receptors (Caterina et al., 1999) and mechanical force, P2X3
Prostaglandin synthesis
Despite the diverse chemical structure of aspirin-like drugs, the antinociceptive effect of NSAIDs is mainly due to their common property of inhibiting cyclooxygenases involved in the formation of prostanoids. Prostanoids are formed by most cells and act as autocrine and paracrine lipid mediators. They are not stored but are synthesized de novo from membrane-released arachidonic acid mobilized by phospholipases (PLA2) when cells are activated by mechanical trauma, cytokines and growth factors,
Central and peripheral antihyperalgesic effects of non-steriodal anti-inflammatory drugs (NSAIDs)
NSAIDs are a disparate group of weakly acidic, highly protein-bound compounds having the common pharmacological property of inhibiting prostaglandin biosynthesis (Smith et al., 1994, Kirtikara et al., 2001). This inhibition results from a variety of effects on cyclooxygenases including the irreversible inactivation of COX (e.g. by aspirin) and reversible competitive inhibition of COX (e.g. with ibuprofen). NSAIDs usually normalise the increased pain threshold associated with inflammation rather
Conclusion
NSAIDs are potent antinociceptive agents, whose efficacy in reducing pain is widely recognized in various pain conditions, including post-surgical pain and chronic pain associated with arthritis and cancer. Although NSAIDs have long been used in clinical practice, opinion on the mechanism of their antihyperalgesic action remains controversial. According to published findings, it appears that the inhibition of prostaglandin synthesis by NSAIDs takes place at the site of peripheral inflammation
Acknowledgment
The work of the authors is supported by the Deutsche Forschungsgemeinschaft (DFG 695/2-1) and the BMBF 01EM0103.
The authors are grateful to Dr. B.G. Woodcock for the valuable editorial assistance with the manuscript.
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