Prostaglandins and cycloxygenases in the spinal cord

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Abstract

The spinal cord is one of the sites where non-steroidal anti-inflammatory drugs (NSAIDs) act to produce analgesia and antinociception. Expression of cyclooxygenase(COX)-1 and COX-2 in the spinal cord and primary afferents suggests that NSAIDs act here by inhibiting the synthesis of prostaglandins (PGs). Basal release of PGD2, PGE2, PGF and PGI2 occurs in the spinal cord and dorsal root ganglia. Prostaglandins then bind to G-protein-coupled receptors located in intrinsic spinal neurons (receptor types DP and EP2) and primary afferent neurons (EP1, EP3, EP4 and IP). Acute and chronic peripheral inflammation, interleukins and spinal cord injury increase the expression of COX-2 and release of PGE2 and PGI2. By activating the cAMP and protein kinase A pathway, PGs enhance tetrodotoxin-resistant sodium currents, inhibit voltage-dependent potassium currents and increase voltage-dependent calcium inflow in nociceptive afferents. This decreases firing threshold, increases firing rate and induces release of excitatory amino acids, substance P, calcitonin gene-related peptide (CGRP) and nitric oxide. Conversely, glutamate, substance P and CGRP increase PG release. Prostaglandins also facilitate membrane currents and release of substance P and CGRP induced by low pH, bradykinin and capsaicin. All this should enhance elicitation and synaptic transfer of pain signals in the spinal cord. Direct administration of PGs to the spinal cord causes hyperalgesia and allodynia, and some studies have shown an association between induction of COX-2, increased PG release and enhanced nociception. NSAIDs diminish both basal and enhanced PG release in the spinal cord. Correspondingly, spinal application of NSAIDs generally diminishes neuronal and behavioral responses to acute nociceptive stimulation, and always attenuates behavioral responses to persistent nociception. Spinal application of specific COX-2 inhibitors sometimes diminishes behavioral responses to persistent nociception.

Introduction

Since it was proposed (Vane, 1971, Ferreira, 1972, Ferreira et al., 1973) that aspirin-like drugs cause analgesia by blocking the synthesis of prostaglandins (PGs), studies on PGs and on pain have fared hand in hand. Jurna (1997) has brought to our attention that in 1926 Hanzlick concluded that ‘the analgesic action of [the salicylates] is mainly central’ and that Woodbury, in the third edition (1965) of Goodman and Gilman's famous The Pharmacological Basis of Therapeutics, noted that ‘the salicylates are capable of alleviating certain types of pain by virtue of a selective depressant effect on the CNS’. And yet in the sixth edition of this textbook (1980) Flower, Moncada and Vane state that ‘aspirin works peripherally’ (Jurna, 1997), more in line with the findings of Lim et al. (1964). However, later experiments demonstrated that aspirin-like drugs, in addition to their peripheral action, indeed have antinociceptive effects by acting upon central nervous system (CNS) structures (Carlsson et al., 1986, Carlsson et al., 1988) including the spinal cord (Jurna et al., 1992, Malmberg and Yaksh, 1992a). Furthermore, the finding that both cyclooxygenase (COX) enzymes, i.e. COX-1 and COX-2 (see, e.g. Kaufmann et al., 1997, Vane et al., 1998), are expressed in the spinal cord has lent support to the idea that the non-steroidal anti-inflammatory drugs (NSAIDs) also act in the spinal cord by inhibiting PG synthesis.

The present review will thus deal with PGs, COXs and non-opioid analgesics from a neurobiological perspective as they involve the spinal cord and related structures. We shall first address the biochemical aspects of PG synthesis and COX molecules, as well as the location of COX-1 and COX-2 and the induction of their expression in the spinal cord. Then the PG types and their release, receptor types, and behavioral and cellular effects will be dealt with. Finally, the spinal effects of COX inhibitors will be reviewed.

Section snippets

Prostaglandins as products of cyclooxygenases

Arachidonic acid, the most abundant precursor of PGs in mammals, is cleaved from cell membrane phospholipids by the action of phospholipase A2 (PLA2) and phospholipase C (PLC) (Fig. 1A) (see Campbell and Halushka, 1996). These phospholipases are activated by a variety of intercellular and intracellular mediators (Axelrod et al., 1988). Arachidonic acid is in turn transformed into PGG2 and then PGH2 by the action of an enzyme variously called prostaglandin endoperoxide synthase, fatty acid

Basal expression and location of the cyclooxygenases

Both COX-1 and COX-2 mRNA and protein are constitutively expressed in brain and spinal cord, although the fact that synaptic activity induces COX-2 expression (Yamagata et al., 1993) may suggest that COX-2 is actually ‘constantly induced’ by neural activity (Section 3.3). These and other findings are presented in detail below. The degree to which expression in the various preparations is really ‘basal’ may of course be subject to discussion.

Prostaglandins in the spinal cord

Once arachidonic acid has given rise to PGH2 by the action of COX (Section 2.1), several enzymes come into play to synthesize the prostanoids. Thus hydroxyl and/or ketone groups are set on the cyclopentane ring to produce PGD2, PGE2 and PGF, and a new ring is formed upon the cyclopentane ring to form prostacyclin (PGI2) (Campbell and Halushka, 1996). Both arachidonic acid and the PGs can then subserve intracellular roles and can also be released into the extracellular space (Axelrod et al.,

Effects of spinal application of cyclooxygenase inhibitors

As mentioned in Sections 1 and 2, the most widely accepted explanation for the anti-inflammatory and analgesic effect of non-opioid analgesics is the inhibition of COX-mediated PG synthesis (Section 5.1), and this also how the NSAIDs are thought to act upon the spinal cord (Section 5.4.1). This explanation, however, leaves several questions unanswered and has thus been the subject of much discussion (cf. McCormack and Brune, 1991, Brune et al., 1993, McCormack, 1994, Geisslinger and Schaible,

Final comments

The story relating spinal COXs and PGs to spinal nociceptive mechanisms is neither complete nor homogeneous. This story is not made of several areas of knowledge whose borders have come to touch and fuse with one another; it is rather made of individual findings that mainly point in the same direction. Indeed, the induction of COX by conditions related to inflammation and pain, the increase in PG release caused by these conditions and by excitatory neuromediators, the enhancement by PGs of

Acknowledgements

Thanks are due for the bibliographic support received from the Thüringer Universitäts- und Landesbibliothek Jena, Zweigbibliothek Medizinisch-Theoretische Institute. The financial support received from the Deutsche Forschungsgemeinschaft, the Alexander-von-Humboldt-Stiftung and the Venezuelan CONICIT is also gratefully acknowledged.

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