Up‐regulation of cyclooxygenase‐2 mRNA in the rat spinal cord following peripheral inflammation

Abstract

Prostaglandins (PG) have been described as mediators in spinal nociceptive processing after peripheral inflammation. Enzymes essential for PG biosynthesis, cyclooxygenase isozymes COX-1 and COX-2, have not yet been investigated in the spinal cord. In two studies on rats with adjuvant-induced peripheral inflammation levels of mRNA expression of both COX isoforms were analyzed in the lumbar section of the spinal curd using reverse transcription-polymerase chain reaction (RT-PCR) technique. We could show that mRNA of both COX isoforms is expressed constitutively in the spinal cord with COX-2 as the predominant isoform. Six hours after induction of peripheral inflammation, levels of COX-2 mRNA expression were raised significantly in respect to untreated control rats and returned to baseline within 3 days after induction of inflammation. COX-2 might therefore be regarded as the COX isozyme responsible for spinal PG release in nociceptive processing under a peripheral inflammatory stimulus.l~ey words: Cyclooxygenase-2; Inflammation; Spinal cord; R F-PCR densa of the kidney [8] the testis or the brain, where COX-2 is not only expressed constitutively but also considered to be the dominating COX isoform [9][10][11]. In the central nervous system (CNS) prostaglandins maintain important functions as neuroregulators [12]. It has been reported that PGs are released from the spinal cord by various processes as stimulation of afferent nerves [13], noxious thermal stimulation [14] and by increased potassium levels [15]. Prostaglandins are also known to be involved in transmission of nociceptive information in the spinal cord after peripheral inflammation [16]. Functional evidence thus indicates a role for cyclooxygenases in the spinal cord, expression of the enzyme itself, however, has not yet been investigated. We conducted two studies to determine the spinal presence and distribution of COX isozymes using the rat model of adjuvant-induced inflammation. Tissue samples of hindpaws and the lumbar section of the spinal cord were taken before and after induction of inflammation and examined for levels of COX mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR).

Spinal inflammatory hyperalgesia is mediated by prostaglandin E receptors of the EP2 subtype

“…17,37). The time course of the analgesic action of celecoxib, with only very little or no analgesic effect during early hyperalgesia (2-4 hours after zymosan A injection) but pronounced analgesia at later stages, nicely corresponds to the time course of spinal PGE 2 production and perfectly matches the fast recovery from inflammatory hyperalgesia in EP2 -/-mice (compare Figures 4 and 5).…”

Induction of Cyclooxygenase-2 Accounts for Restraint Stress-Induced Oxidative Status in Rat Brain

“…COX-2, although an inducible protein, is constitutively expressed in only a few tissues including the brain, particularly in neuronal soma, not in astrocytes, of different regions including cortex, amygdala, hippocampal formation, and the dorsal horn of the spinal cord (Yamagata et al, 1993;Breder et al, 1995). It becomes upregulated brieflyFafter 1-8 hFafter seizure, trauma, intracerebral hemorrhage, ischemia, or other neurodegenerative diseases (Yamagata et al, 1993;Beiche et al, 1996;Nogawa et al, 1998;Knott et al, 2000;Kim et al, 2001;Gong et al, 2001). Other types of brain cells, including microglia, astrocytes, and vascular cells, do not express significant levels of COX-2 normally, but its expression is also increased after cerebral insults (Laflamme et al, 1999).…”

Nociception in cyclooxygenase isozyme-deficient mice

“…However, COX-2 is also constitutively expressed in human brain in amounts equal to COX-1 (12), and it is the predominant isoform in the spinal cord of the rat (13). Rat stomach tissue microsomes constitutively express about 5% of COX as COX-2 protein (22), and the macula densa of the rat kidney expresses constitutive COX-2 that is up-regulated by salt deprivation (23).…”

“…All sensory pathways synapse in the dorsal horn of the spinal cord, and most have synapses in the thalamus and periaqueductal gray matter of the midbrain. COX-1 and COX-2 both have been identified in the brain and spinal cord of humans and rats; COX-2, as well as COX-1, is constitutively expressed (12)(13)(14). It is likely, therefore, that PGs made by both COX enzymes are involved in hyperalgesia.…”