Inﬂammation causes an increased synthesis of COX-2-dependent prostaglan- dins, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity. Prostaglandins regulate the sensitivity of so-called poly- modal nociceptors that are present in nearly all tissues. A signiﬁcant portion of these nociceptors cannot be easily activated by physiological stimuli such as mild pressure or some increase of temperature (Schaible and Schmidt 1988).
Fig. 2 Scheme of the distribution of acidic antipyretic analgesics in the human body (trans- position of the data from animal experiments to human conditions). Dark areas indicate high concentrations of acidic antipyretic analgesics, i.e., stomach and upper wall of the gastrointestinal tract, blood, liver, bone marrow, spleen (not shown), and inﬂamed tissue (e.g., joints), as well as the kidney (cortex>medulla). Some acidic antipyretic analgesics are excreted in part unchanged in urine and achieve high concentration in this body ﬂuid, oth- ers encounter enterohepatic circulation and are found in high concentrations as conjugates in the bile
However, following tissue trauma and subsequent release of prostaglandins, “silent” polymodal nociceptors become excitable to pressure, temperature changes, and tissue acidosis (Neugebauer et al. 1995). This process results in a phenomenon called hyperalgesia—in some instances allodynia.
Prostaglandin E2 and other inﬂammatory mediators facilitate the activa- tion of tetrodotoxin-resistant Na+ channels in dorsal root ganglion neurons
(Akopian et al. 1996; England et al. 1996; Gold et al. 1996). Compelling evi- dence indicates that small dorsal root ganglion neurons are the somata which give rise to thinly and unmyelinated C and Aδ nerve ﬁbers, both conducting nociceptive stimuli. Increased opening of these Na+ channels involves activa- tion of the adenylyl cyclase enzyme and increases in cAMP possibly leading to protein kinase A-dependent phosphorylation of the channels. Meanwhile, two sensory neuron-speciﬁc tetrodotoxin-resistant sodium channel α-subunits, Nav1.8 and Nav1.9, have been characterized in dorsal root ganglia (Benn et al.
2001). Another important target of protein kinase A-mediated phosphoryla-
tion is the capsaicin receptor ( transient receptor potential vanilloid 1, TRPV1), a nonselective cation channel of sensory neurons involved in the sensation of temperature and inﬂammatory pain (Lopshire and Nicol 1997; Caterina et al.
2000; Davis et al. 2000). TRPV1 responds to temperature above 40°C and to noxious stimuli including capsaicin, the pungent component of chili peppers,
and extracellular acidiﬁcation. On the basis of this mechanism, prostaglandins produced during inﬂammatory states may signiﬁcantly increase the excitabil- ity of nociceptive nerve ﬁbers, including reactivity to temperatures below 40°C
(i.e., body temperature), thereby contributing to the activation of “sleeping” nociceptors and the development of burning pain. As such, it appears rea- sonable that at least a part of the peripheral antinociceptive action of acidic
antipyretic analgesics arises from prevention of this peripheral sensitization.
Apart from sensitizing peripheral nociceptors, prostaglandins act in the central nervous system to produce central hyperalgesia. Experimental data suggest that both acidic and nonacidic COX inhibitors antagonize central hy- peralgesia in the dorsal horn of the spinal cord by modulating the glutamatergic signal transfer from nociceptive C ﬁbers to secondary neurons, which prop- agate the signals to the higher centers of the central nervous system. Some COX-2 is expressed constitutively in the dorsal horn of the spinal cord, and becomes upregulated brieﬂy after a trauma, such as damage to a limb, in the corresponding sensory segments of the spinal cord (Beiche et al. 1996). The induction of spinal cord COX-2 expression may facilitate transmission of the nociceptive input. In line with a role of COX-2 in central pain percep- tion, Smith et al. (1998) reported that selective COX-2 inhibition suppressed inﬂammation-induced prostaglandin levels in cerebrospinal ﬂuid, whereas se- lective inhibition of COX-1 was inactive in this regard. These observations were substantiated by ﬁndings showing a widespread induction of COX-2 expres- sion in spinal cord neurons and in other regions of the central nervous system following peripheral inﬂammation (Samad et al. 2001).
Fig. 3a, b Molecular mechanisms underlying peripheral and central hyperalgesia elicited by prostaglandin E2 (adapted from Brune and Zeilhofer 2006). a In the periphery, prostaglandin E2 increases excitability of nociceptor endings via cyclic AMP-protein kinase A-dependent activation of tetrodotoxin-resistant sodium channels (Nav 1.8, Nav 1.9) or the capsaicin re- ceptor TRPV1 (nonselective cation channel). b The central component of inﬂammatory pain originates from a disinhibition of dorsal horn neurons, which are relieved from glycinergic neurotransmission by prostaglandin E2 . The latter activates EP2 receptors thereby leading to a protein kinase A-dependent phosphorylation and inhibition of glycine receptors con- taining the α3 subunit (GlyRα3). Moreover, prostaglandin E2 acting via EP2 receptors has been shown to directly depolarize spinal neurons
Several mechanisms have been proposed to underlie the facilitatory ac- tion of prostaglandin E2 on central pain sensation. Baba et al. (2001) showed that prostaglandin E2 at relatively high concentrations directly depolarizes wide dynamic range neurons in the deep dorsal horn. More convincingly, prostaglandin E2 at signiﬁcantly lower concentrations reduces the inhibitory tone of the neurotransmitter glycine onto neurons in the superﬁcial layers of the dorsal horn (Ahmadi et al. 2002) by phosphorylation of the speciﬁc glycine
receptor subtype GlyR α3 (Harvey et al. 2004), thereby causing a disinhibition of spinal nociceptive transmission. In a recent study, the same group has iden-
tiﬁed PGE2 receptors of the EP2 receptor subtype as key signaling elements in spinal inﬂammatory hyperalgesia (Reinold et al. 2005), thus opening new avenues for the development of new analgesics. The current understanding of the molecular mechanisms underlying peripheral and central hyperalgesia elicited by prostaglandin E2 are summarized in Fig. 3.