Effect of spinal cyclooxygenase inhibitors in rat using the formalin test and in vitro prostaglandin E2 release

Dirig, David M.; Konin, Gabrielle P.; Isakson, Peter C.; Yaksh, Tony L.

doi:10.1016/s0014-2999(97)01053-4

Cited by 66 publications

(34 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A more likely scenario is that several linoleic acid metabolites contribute to TRPV1 activation. It is also possible that other factors capable of sensitizing TRPV1 (15)(16) were coreleased under these conditions. Thus, the resultant TRPV1 agonist activity could be an entourage effect of several lipids acting in concert.…”

Section: Discussionmentioning

confidence: 99%

Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia

Patwardhan¹,

Scotland

Akopian³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

196

191

View full text Add to dashboard Cite

Transient receptor potential vanilloid 1 (TRPV1) plays a major role in hyperalgesia and allodynia and is expressed both in the peripheral and central nervous systems (CNS). However, few studies have evaluated mechanisms by which CNS TRPV1 mediates hyperalgesia and allodynia after injury. We hypothesized that activation of spinal cord systems releases endogenous TRPV1 agonists that evoke the development of mechanical allodynia by this receptor. Using in vitro superfusion, the depolarization of spinal cord triggered the release of oxidized linoleic acid metabolites, such as 9-hydroxyoctadecadienoic acid (9-HODE) that potently activated spinal TRPV1, leading to the development of mechanical allodynia. Subsequent calcium imaging and electrophysiology studies demonstrated that synthetic oxidized linoleic acid metabolites, including 9-HODE, 13-HODE, and 9 and 13-oxoODE, comprise a family of endogenous TRPV1 agonists. In vivo studies demonstrated that intrathecal application of these oxidized linoleic acid metabolites rapidly evokes mechanical allodynia. Finally, intrathecal neutralization of 9-and 13-HODE by antibodies blocks CFA-evoked mechanical allodynia. These data collectively reveal a mechanism by which an endogenous family of lipids activates TRPV1 in the spinal cord, leading to the development of inflammatory hyperalgesia. These findings may integrate many pain disorders and provide an approach for developing analgesic drugs.inflammation ͉ pain T ransient receptor potential vanilloid 1 (TRPV1) plays a pivotal role in many pain models, leading to the development of hyperalgesia and/or allodynia (1-2). TRPV1 is expressed in the peripheral as well as central nervous systems (CNS) including several areas involved in nociceptive transmission (3). Numerous studies have demonstrated that peripheral TRPV1 is activated by noxious heat and protons and is regulated by endogenous ligands (2), contributing to peripheral mechanisms of heat hyperalgesia (4). However, TRPV1 is also expressed in the CNS, where comparatively little is known about the role of this receptor in mediating central pain mechanisms.Recent studies have used TRPV1 antagonists to evaluate the role of CNS TRPV1 in inflammatory hyperalgesia. Interestingly, the systemic/spinal administration of TRPV1 antagonists blocks inflammation-induced heat hyperalgesia, as well as mechanical allodynia (5-6). These findings were unexpected since TRPV1 is not activated by mechanical stimuli, suggesting that spinal TRPV1 activation leads to central sensitization to both thermal and mechanical stimuli (7-8). Based upon these observations, we hypothesized that the afferent barrage resulting from peripheral tissue injury leads to generation of endogenous TRPV1 ligands in the spinal cord that activate TRPV1 in the CNS resulting in central sensitization. Results Depolarization of Spinal Cord Results in the Release of EndogenousTRPV1 Ligands. To evaluate the hypothesis that endogenous TRPV1 agonists are released from spinal cord neurons, freshly isolated male rat spinal cords w...

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia

Patwardhan¹,

Scotland

Akopian³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

196

191

View full text Add to dashboard Cite

show abstract

“…It is quite surprising to see that rofecoxib was analgesic in the first phase (acute) of the formalin test since COX-2 is expressed at very low levels in the periphery. However, induction of COX-2 expression may be increased by peripheral injury, leading to the development of COX-2 inhibitor sensitivity that may or may not be observed within the one hour window of the formalin test (Dirig et al, 1997). Furthermore, the same authors have already demonstrated that an acute stimulus, such as intraplantar injection of formalin, could lead to an immediate increase in prostaglandin (PG) release (Dirig et al, 1997).…”

Section: Local Antinociceptive Effect Of Nsaidsmentioning

confidence: 99%

“…However, induction of COX-2 expression may be increased by peripheral injury, leading to the development of COX-2 inhibitor sensitivity that may or may not be observed within the one hour window of the formalin test (Dirig et al, 1997). Furthermore, the same authors have already demonstrated that an acute stimulus, such as intraplantar injection of formalin, could lead to an immediate increase in prostaglandin (PG) release (Dirig et al, 1997). It is suggested that this increased PGE 2 release is mediated by COX-2 and not COX-1 pharmacology, and because the effects are observed acutely, this COX-2 must by definition be constitutively expressed (Ghilardi et al, 2004).…”

Section: Local Antinociceptive Effect Of Nsaidsmentioning

confidence: 99%

“…Finally, in a study by Yamamoto and Nozaki-Taguchi (2002), intrathecal administration of celecoxib and indomethacin was associated with a significant decrease in the number of flinching in both phase 1 and 2 of the formalin test compared to vehicle-treated rats, although it was not significant for the first phase when the two drugs were administered orally. Considering suggestions from Dirig et al (1997) and Ghilardi et al (2004) mentioned above, it is possible that intraplantar injection of NaCl 0.9% and rofecoxib or NS-398 15 min prior to injection of formalin may have induced COX-2 expression locally.…”

Section: Local Antinociceptive Effect Of Nsaidsmentioning

confidence: 99%

See 1 more Smart Citation

Synergistic antinociceptive effects of anandamide, an endocannabinoid, and nonsteroidal anti-inflammatory drugs in peripheral tissue: A role for endogenous fatty-acid ethanolamides?

Guindon

LoVerme

Léan

et al. 2006

European Journal of Pharmacology

View full text Add to dashboard Cite

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit fatty-acid amide hydrolase (FAAH), the enzyme responsible for the metabolism of anandamide, an endocannabinoid. It has been suggested that the mechanisms of action of NSAIDs could be due to inhibition of cyclooxygenase (COX) and also to an increase in endocannabinoid concentrations. In a previous study we have demonstrated that the local analgesic interaction between anandamide and ibuprofen (a non-specific COX inhibitor) was synergistic for the acute and inflammatory phases of the formalin test. To test this hypothesis further, we repeated similar experiments with rofecoxib (a selective COX-2 inhibitor) and also measured the local concentrations of anandamide, and of two fatty-acid amides, oleoylethanolamide and palmitoylethanolamide. We established the ED 50 for anandamide (34.52 pmol ± 17.26) and rofecoxib (381.72 pmol ± 190.86) and showed that the analgesic effect of the combination was synergistic. We also found that paw tissue levels of anandamide, oleoylethanolamide and palmitoylethanolamide were significantly higher when anandamide was combined with NSAIDs and that this effect was greater with rofecoxib. In conclusion, local injection of anandamide or rofecoxib was antinociceptive in a test of acute and inflammatory pain and the combination of anandamide with rofecoxib was synergistic. Finally, locally injected anandamide with either NSAID (ibuprofen or rofecoxib) generates higher amount of fatty-acid ethanolamides. The exact comprehension of the mechanisms involved needs further investigation.

show abstract

“…A central analgesic effect of NSAIDs Ž has also been proposed McCormak, 1994;Cashman, 1996;. Yaksh et al, 1998 , which is probably mediated by regula-Ž tion of cyclooxygenase-2 activity in the spinal cord Dirig . et al, 1997;Smith et al, 1998 .…”

Section: Introductionmentioning

confidence: 99%

Regulation of cyclooxygenase activity by metamizol

Campos

Gregorio

Garcı́a-Nieto

et al. 1999

European Journal of Pharmacology

View full text Add to dashboard Cite

The ability of metamizol to inhibit cyclooxygenase-1 and cyclooxygenase-2 activities has been evaluated using different cyclooxygenase sources. Metamizol inhibited purified cyclooxygenase-1 and cyclooxygenase-2 with an IC of about 150 mgrml. A similar IC 50 50value for cyclooxygenase-2 was obtained in lipopolysaccharide-activated broken murine macrophages. Consistent with these findings, molecular models of the complexes between cyclooxygenase-1 or cyclooxygenase-2 with 4-methylaminoantipyrine, the major active derivative of metamizol, suggested a common binding mode to both isoforms. In intact cells, however, the inhibition profiles were Ž . markedly different. The IC values of metamizol for cyclooxygenase-1 in intact bovine aortic endothelial cells BAEC cells and human 50 platelets were 1730 " 150 mgrml and 486 " 56 mgrml, respectively. Inhibition of cyclooxygenase-2 activity in murine macrophages and primary human leukocytes activated by lipopolysaccharide yielded IC values of 12 " 1.8 mgrml and 21 " 2.9 mgrml, 50 respectively. These data indicate that the IC values obtained with purified enzymes or disrupted cells cannot always be extrapolated to 50 Ž . the cyclooxygenase inhibitory activity of nonsteroidal antiinflammatory drugs NSAIDs in intact cells. The data presented here also indicate that cyclooxygenase-2 inhibition could play an important role in the pharmacological effects of metamizol. q 1999 Elsevier Science B.V. All rights reserved.Ž .

show abstract

Effect of spinal cyclooxygenase inhibitors in rat using the formalin test and in vitro prostaglandin E2 release

Cited by 66 publications

References 30 publications

Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia

Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia

Synergistic antinociceptive effects of anandamide, an endocannabinoid, and nonsteroidal anti-inflammatory drugs in peripheral tissue: A role for endogenous fatty-acid ethanolamides?

Regulation of cyclooxygenase activity by metamizol

Contact Info

Product

Resources

About