Constitutive Spinal Cyclooxygenase-2 Participates in the Initiation of Tissue Injury-Induced Hyperalgesia

Ghilardi, Joseph R.; Svensson, Camilla I.; Rogers, Scott D.; Yaksh, Tony L.; Mantyh, Patrick W.

doi:10.1523/jneurosci.5054-03.2004

Cited by 93 publications

(64 citation statements)

References 27 publications

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“…Prolonged barrage of incoming signals from nociceptors causes activation and sensitization of nociceptive neurons (Ji et al, 2003) and activation of glial cells (Samad et al, 2001, Ghilardi et al, 2004 in the spinal dorsal horn. With time, local prostaglandin release from the activated neurons and glia becomes essential for the maintenance of sensitization of adjacent nociceptive neurons [You, 2003 #16157;Watkins, 2001 #8080;Watkins, 2001 #8081].…”

Section: Discussionmentioning

confidence: 99%

Sensitization of central trigeminovascular neurons: Blockade by intravenous naproxen infusion

Jakubowski¹,

Levy²,

Kainz³

et al. 2007

Neuroscience

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We have previously observed that migraine attacks impervious to triptan therapy were readily terminated by subsequent intravenous administration of the non-steroidal anti-inflammatory drug (NSAID) ketorolac. Since such attacks were associated with periorbital allodynia -a symptom of central sensitization -we examined whether infusion of the NSAID naproxen can block sensitization of central trigeminovascular neurons in the medullary dorsal horn, using in vivo single-unit recording in the rat. Topical exposure of the cerebral dura to inflammatory soup (IS) for 5 min resulted in a short-term burst of activity (<8 min) and a long-lasting (>120 min) neuronal hyper-responsiveness to stimulation of the dura and periorbital skin (group 1). Infusion of naproxen (1 mg/kg) 2 h after IS (group 1) brought all measures of neuronal responsiveness back to the baseline values recorded prior to IS, and depressed ongoing spontaneous activity well below baseline. When given preemptively 1 h before IS (group 2), naproxen blocked the short-term burst of activity and every long-term measure of neuronal hyper-responsiveness that was studied in the central neurons. The same preemptive treatment, however, failed to block IS-induced short-term burst of activity in C-unit meningeal nociceptors (group 3). The results suggest that parenteral administration of naproxen, unlike triptan therapy, can exert direct inhibition over central trigeminovascular neurons in the dorsal horn. Though impractical as a routine migraine therapy, parenteral NSAID administration should be useful as a non-narcotic rescue therapy for migraine in the setting of the emergency department.

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Section: Discussionmentioning

confidence: 99%

Sensitization of central trigeminovascular neurons: Blockade by intravenous naproxen infusion

Jakubowski¹,

Levy²,

Kainz³

et al. 2007

Neuroscience

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“…At the end of the formalin test, paw oedema was measured at the base of the right hind paw using a digital micrometer (Mitutoyo Corporation, USA) with an instrumental error of ± (maximum measuring length/75) μm and a resolution of 0.001 mm (Nackley et al, 2003;Ghilardi et al, 2004).…”

Section: Paw Oedemamentioning

confidence: 99%

“…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). Indeed, in many peripheral tissues COX-2 is normally expressed at very low levels but is dramatically upregulated after tissue injury (Ghilardi et al, 2004).…”

Section: Local Antinociceptive Effect Of Nsaidsmentioning

confidence: 99%

“…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). Indeed, in many peripheral tissues COX-2 is normally expressed at very low levels but is dramatically upregulated after tissue injury (Ghilardi et al, 2004). Other authors have suggested that products of COX-2 can be released in the injected paw immediately after formalin injection and that intraplantar injection of celecoxib completely inhibited development of secondary hyperalgesia (Veiga et al, 2004).…”

Section: Local Antinociceptive Effect Of Nsaidsmentioning

confidence: 99%

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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

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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.

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“…Expression of COX-2 protein in naïve rat spinal cord has been profiled by others, with agreement that it is expressed in dorsal and ventral horn neurons (16) and some debate regarding any presence in radial glia (18), astrocytes (19), or endothelial cells (20). In our experiments, we saw that spinal cords from control and diabetic rats showed COX-2 immunoreactivity only in dorsal horn neurons, motor neurons, and oligodendrocytes, indicating that the increased COX-2 protein and activity observed in diabetes does not involve induction of COX-2 expression in novel cell types.…”

Section: Discussionmentioning

confidence: 75%

Pathogenesis of Spinally Mediated Hyperalgesia in Diabetes

Ramos

Jiang²,

Svensson³

et al. 2007

Diabetes

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Hyperalgesia to noxious stimuli is accompanied by increased spinal cyclooxygenase (COX)-2 protein in diabetic rats. The present studies were initiated to establish causality between increased spinal COX-2 activity and hyperalgesia during diabetes and to assess the potential involvement of polyol pathway activity in the pathogenesis of spinally mediated hyperalgesia. Rats with 1, 2, or 4 weeks of streptozotocin-induced diabetes exhibited significantly increased levels of spinal COX-2 protein and activity, along with exaggerated paw flinching in response to 0.5% paw formalin injection. Increased flinching of diabetic rats was attenuated by intrathecal pretreatment with a selective COX-2 inhibitor immediately before formalin injection, confirming the involvement of COX-2 activity in diabetic hyperalgesia. Chronic treatment with insulin or ICI222155, an aldose reductase inhibitor (ARI) previously shown to prevent spinal polyol accumulation and formalinevoked hyperalgesia in diabetic rats, prevented elevated spinal COX-2 protein and activity in diabetic rats. In contrast, the ARI IDD676 had no effect on spinal polyol accumulation, elevated spinal COX-2, or hyperalgesia to paw formalin injection. In the spinal cord, aldose reductase immunoreactivity was present solely in oligodendrocytes, which also contained COX-2 immunoreactivity. Polyol pathway flux in spinal oligodendrocytes provides a pathogenic mechanism linking hyperglycemia to hyperalgesia in diabetic rats. Diabetes 56: [1569][1570][1571][1572][1573][1574][1575][1576] 2007 A proportion of diabetic patients experience chronic pain that severely degrades their quality of life. The pathogenesis of painful diabetic neuropathy is unclear, and treatment options are currently limited to palliatives that do not target a pathogenic mechanism specific to painful diabetic neuropathy and provide limited efficacy before side effects become intolerable (1). Experimental models of diabetic neuropathy can spur development of novel therapies by providing an understanding of how diabetes alters sensory processing.Diabetic rats display abnormal pain-associated behaviors, measured as exaggerated responses to painful stimuli (hyperalgesia) or nocifensive responses to normally innocuous stimuli (allodynia). Hyperalgesia to paw formalin injection (2,3) and allodynia to tactile stimulation of the paw (4) develop within weeks of induction of hyperglycemia, and, as overt structural pathology in peripheral nerves is minimal, attention has focused on biochemical disorders that could exaggerate sensory processing.The formalin test is used to investigate spinal sensitization in animals (5) and allows investigation of sensory processing beyond peripheral nociceptive pathways. Diabetic rats exhibit increased nocifensive behavior during periods of the formalin test associated with spinal sensitization (6,7) in concert with paradoxically decreased spinal release of excitatory neurotransmitters (8,9). This suggests that hyperalgesia is not caused by increased primary afferent input and, toge...

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Constitutive Spinal Cyclooxygenase-2 Participates in the Initiation of Tissue Injury-Induced Hyperalgesia

Cited by 93 publications

References 27 publications

Sensitization of central trigeminovascular neurons: Blockade by intravenous naproxen infusion

Sensitization of central trigeminovascular neurons: Blockade by intravenous naproxen infusion

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

Pathogenesis of Spinally Mediated Hyperalgesia in Diabetes

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