Mechanisms of Hyperalgesia

16 May

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).

Mechanisms of Hyperalgesia

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.

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