Peripheral inflammatory hyperalgesia depends on the COX increase in the dorsal root ganglion

Abstract

It is well established that dorsal root ganglion (DRG) cells synthesize prostaglandin. However, the role that prostaglandin plays in the inflammatory hyperalgesia of peripheral tissue has not been established. Recently, we have successfully established a technique to inject drugs (3 μL) directly into the L5-DRG of rats, allowing in vivo identification of the role that DRG cell-derived COX-1 and COX-2 play in the development of inflammatory hyperalgesia of peripheral tissue. IL-1β (0.5 pg) or carrageenan (100 ng) was administered in the L5-peripheral field of rat hindpaw and mechanical hyperalgesia was evaluated after 3 h. Administration of a nonselective COX inhibitor (indomethacin), selective COX-1 (valeryl salicylate), or selective COX-2 (SC-236) inhibitors into the L5-DRG prevented the hyperalgesia induced by IL-1β. Similarly, oligodeoxynucleotide-antisense against COX-1 or COX-2, but not oligodeoxynucleotide-mismatch, decreased their respective expressions in the L5-DRG and prevented the hyperalgesia induced by IL-1β in the hindpaw. Immunofluorescence analysis demonstrated that the amount of COX-1 and COX-2, constitutively expressed in TRPV-1 + cells of the DRG, significantly increased after carrageenan or IL-1β administration. In addition, indomethacin administered into the L5-DRG prevented the increase of PKCe expression in DRG membrane cells induced by carrageenan. Finally, the administration of EP1/EP2 (7.5 ng) or EP4 (10 μg) receptor antagonists into L5-DRG prevented the hyperalgesia induced by IL-1β in the hindpaw. In conclusion, the results of this study suggest that the inflammatory hyperalgesia in peripheral tissue depends on activation of COX-1 and COX-2 in C-fibers, which contribute to the induction and maintenance of sensitization of primary sensory neurons.D uring tissue injury, prostaglandin-E 2 (PGE 2 ) is produced by the activation of the enzyme cyclooxygenase (COX) to play an important role in inflammatory hyperalgesia. PGE 2 sensitizes peripheral nociceptors through the activation of PGE 2 receptors (EP) (1). This sensitization, characterized by a reduction of nociceptive threshold and by an increase in peripheral afferent neuron responsiveness, is the main feature of inflammatory hyperalgesia in the peripheral tissue. The widespread use of nonsteroidal antiinflammatory drugs to control inflammatory hyperalgesia exemplifies the relevance of PGE 2 for the development of inflammatory hyperalgesia. These drugs decrease peripheral inflammatory hyperalgesia by inhibiting COX and, therefore, by preventing the synthesis of PGE 2 (2, 3).The COX enzyme is expressed in two major isoforms, COX-1 and COX-2, with different biological functions (4), although both play a role in the inflammatory hyperalgesia (5, 6). The isoform of COX constitutively expressed in dorsal root ganglion (DRG) is still unclear. Although COX-1 mRNA and, to a lesser extent, COX-2 mRNA have been detected in DRG cultures (7) under basal conditions, immunohistochemical studies have shown that DRG cells express only COX-1, but not C...

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Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti‐inflammatory drug‐dependent gastrointestinal damage

“…Nevertheless, systematic modification of the alkyl substituent of the carbamate group progressively enhanced potency at the 3 targets, eventually yielding a balanced multiple ligand that inhibited each of the enzymes with high potency (ARN2508; Table 1). In the lead optimization process, which will be reported elsewhere, we pursued concomitant Cox‐1/Cox‐2 inhibition because both isoforms contribute to inflammatory hyperalgesia (31).…”

“…In the optimization process that led to the identification of ARN2508, we pursued concomitant Cox‐1/Cox‐2 inhibition because both isoforms of this enzyme are known to contribute to the development of inflammatory hyperalgesia (31). Nevertheless, dual FAAH/Cox ligands that selectively recognize either isoform would be experimentally useful to elucidate possible select functional interactions of FAAH substrates with Cox‐1‐ or Cox‐2‐derived prostanoids.…”

“…The compound obtained (compound 3; 1). In the lead optimization process, which will be reported elsewhere, we pursued concomitant Cox-1/Cox-2 inhibition because both isoforms contribute to inflammatory hyperalgesia (31).…”

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