COX-dependent mechanisms involved in the antinociceptive action of NSAIDs at central and peripheral sites

Abstract

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 prostaglandins. Prostaglandins are potent hyperalgesic mediators which modulate multiple sites along the nociceptive pathway and enhance both transduction (peripheral sensitizing effect) and transmission (central sensitizing effect) of nociceptive information. Inhibition of the formation of prostaglandins at peripheral and central sites by NSAIDs thus leads to the normalisation of the increased pain threshold associated with inflammation. The contribution of peripheral and central mechanisms to the overall antinociceptive action of NSAIDs depends on several factors including the location of the targets of drug action, the site of drug delivery and the uptake and distribution to the site of action.

The present work reviews the data on the regulation and location of cyclooxygenases at central and peripheral sites of the nociceptive pathway and focuses on the role of COX in the generation and maintenance of pain hypersensitivity. Experimental and clinical evidences are used to evaluate the significance of the peripheral and central antihyperalgesic effects of NSAIDs.

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.