Prostaglandins and cycloxygenases in the spinal cord

The spinal cord is one of the sites where non-steroidal anti-inflammatory d rugs (NSAIDs) act to produce analgesia and antinociception. Expression of c yclooxygenase(COX)-1 and COX-2 in the spinal cord and primary afferents sug gests that NSAIDs act here by inhibiting the synthesis of prostaglandins (P Gs). Basal release of PGD(2), PGE(2), PGF(2 alpha) and PGI(2) 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 a nd EP2) and primary afferent neurons (EP1, EP3, EP4 and IF). Acute and chro nic peripheral inflammation, interleukins and spinal cord injury increase t he expression of COX-2 and release of PGE(2) and PGI(2). By activating the cAMP and protein kinase A pathway, PGs enhance tetrodotoxin-resistant sodiu m currents, inhibit voltage-dependent potassium currents and increase volta ge-dependent calcium inflow in nociceptive afferents. This decreases firing threshold, increases firing rate and induces release of excitatory amino a cids, substance P, calcitonin gene-related peptide (CGRP) and nitric oxide. Conversely, glutamate, substance P and CGRP increase PG release. Prostagla ndins also facilitate membrane currents and release of substance P and CGRP induced by low pH, bradykinin and capsaicin. All this should enhance elici tation and synaptic transfer of pain signals in the spinal cord. Direct adm inistration of PGs to the spinal cord causes hyperalgesia and allodynia, an d some studies have shown an association between induction of COX-2, increa sed PG release and enhanced nociception. NSAIDs diminish both basal and enh anced PG release in the spinal cord. Correspondingly, spinal application of NSAIDs generally diminishes neuronal and behavioral responses to acute noc iceptive stimulation, and always attenuates behavioral responses to persist ent nociception. Spinal application of specific COX-2 inhibitors sometimes diminishes behavioral responses to persistent nociception. (C) 2001 Elsevie r Science Ltd. All rights reserved.