Spinal Antinociceptive Effect of Epidural Nonsteroidal Antiinflammatory Drugs on Nitric Oxide-induced Hyperalgesia in Rats

Chronic neuroinflammation plays an important role in the development and maintenance of neuropathic pain. The compound flexibilide, which can be obtained from cultured soft coral, possesses anti-inflammatory and analgesic effects in the rat carrageenan peripheral inflammation model. In the present study, we investigated the antinociceptive properties of flexibilide in the rat chronic constriction injury (CCI) model of neuropathic pain. First, we found that a single intrathecal (i.t.) administration of flexibilide significantly attenuated CCI-induced thermal hyperalgesia at 14 days after surgery. Second, i.t. administration of 10-μg flexibilide twice daily was able to prevent the development of thermal hyperalgesia and weight-bearing deficits in CCI rats. Third, i.t. flexibilide significantly inhibited CCI-induced activation of microglia and astrocytes, as well as the upregulated proinflammatory enzyme, inducible nitric oxide synthase, in the ipsilateral spinal dorsal horn. Furthermore, flexibilide attenuated the CCI-induced downregulation of spinal transforming growth factor-β1 (TGF-β1) at 14 days after surgery. Finally, i.t. SB431542, a selective inhibitor of TGF-β type I receptor, blocked the analgesic effects of flexibilide in CCI rats. Our results suggest that flexibilide may serve as a therapeutic agent for neuropathic pain. In addition, spinal TGF-β1 may be involved in the anti-neuroinflammatory and analgesic effects of flexibilide.

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“…Systemic or i.t. administration of nitroglycerin, an NO donor, induces hyperalgesia in rats [32,86,87]. Further, i.t.…”

Section: Discussionmentioning

confidence: 99%

“…Intrathecal (i.t.) administration of nitroglycerin, an NO donor, produces thermal hyperalgesia in rats [32]. Inhibition of spinal NO synthesis also reduces neuropathic pain [31,33].…”

Section: Introductionmentioning

confidence: 99%

Flexibilide Obtained from Cultured Soft Coral Has Anti-Neuroinflammatory and Analgesic Effects through the Upregulation of Spinal Transforming Growth Factor-β1 in Neuropathic Rats

Chen

Huang

et al. 2014

Marine Drugs

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“…It should be acknowledged that there is some evidence suggesting that spinal NO may be involved in pain induction. In this regard, epidural injection of L-arginine produces a slowly developing thermal hyperalgesia in rats (Masue et al, 1999). Also, intrathecal administration of NOS inhibitors attenuates hyperalgesia and allodynia caused by inflammation in rats (Meller et al, 1992).…”

Section: No Mediates the Effect Of Dpdpe On Dorsal Horn Neurons 1025mentioning

confidence: 98%

Role of Spinal Nitric Oxide in the Inhibitory Effect of [d-Pen²,d-Pen⁵]-Enkephalin on Ascending Dorsal Horn Neurons in Normal and Diabetic Rats

Khan

Li²,

Chen³

et al. 2002

J Pharmacol Exp Ther

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Intrathecal [D-Pen2 ,D-Pen 5 ]-enkephalin (DPDPE; a ␦-opioid agonist) has a profound antinociceptive effect in neuropathic pain. Spinal nitric oxide (NO) has been implicated in the analgesic effect of several G protein-coupled receptor agonists. Little, however, is known about the role of spinal NO in the inhibitory effect of DPDPE on spinal dorsal horn neurons. In the present study, we determined the role of NO in the inhibitory effect of DPDPE on ascending dorsal horn neurons in normal rats and in a rat model of diabetic neuropathic pain. Single-unit activity of ascending dorsal horn neurons was recorded in anesthetized rats. The responses of dorsal horn neurons to graded mechanical stimuli and von Frey filaments were determined before and after local spinal application of 0.1 to 5 M DPDPE. The influence of an NO synthase inhibitor, 1-(2-trifluoromethylphenyl) imidazole (TRIM; 30 M), on the effect of DPDPE was then studied in separate groups of dorsal horn neurons in normal and diabetic rats. DPDPE inhibited the response of dorsal horn neurons in both normal and diabetic rats in a concentrationdependent fashion. The inhibitory effect of 1 M DPDPE was abolished by 1 M naltrindole, a ␦-opioid antagonist. Furthermore, the inhibitory effect of DPDPE on the evoked response of dorsal horn neurons was largely eliminated by TRIM in normal and diabetic rats. These data suggest that DPDPE has a profound inhibitory effect on dorsal horn neurons in normal and diabetic rats. Spinal endogenous NO is essential for the inhibitory effect of DPDPE on ascending dorsal horn neurons in both normal and diabetic rats.

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“…Therefore, it is expected to diffuse through the meninges into the CSF after epidural injection and distribute to the lipid constituents of the spinal cord. Masue et al 3 , in a rat model of NO-induced hyperalgesia, have demonstrated that NSAIDs have anti-nociceptive effects when administered epidurally. Malmberg and Yaksh 16,19 have shown that ketorolac administered via the spinal route in rats had analgesic effects and was not neurotoxic.…”

Section: Discussionmentioning

confidence: 99%

“…1 Although NSAIDs are classified as peripheral analgesics, some experimental studies have revealed central analgesic effects when administered via intrathecal, epidural or intracerebroventricular routes. [2][3][4][5] NSAIDs exhibit 100-to 1000-fold increase in their analgesic effects when administered via these routes compared to systemic doses. 2 Wang et al 6 studied the analgesic effects of epidural ibuprofen and argued that the primary site of action could be the spinal cord.…”

Section: Introductionmentioning

confidence: 99%

Epidural lornoxicam administration – innocent

Canduz

Aktuğ

Mavioğlu

et al. 2007

Journal of Clinical Neuroscience

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Spinal Antinociceptive Effect of Epidural Nonsteroidal Antiinflammatory Drugs on Nitric Oxide-induced Hyperalgesia in Rats

Cited by 24 publications

References 39 publications

Flexibilide Obtained from Cultured Soft Coral Has Anti-Neuroinflammatory and Analgesic Effects through the Upregulation of Spinal Transforming Growth Factor-β1 in Neuropathic Rats

Flexibilide Obtained from Cultured Soft Coral Has Anti-Neuroinflammatory and Analgesic Effects through the Upregulation of Spinal Transforming Growth Factor-β1 in Neuropathic Rats

Role of Spinal Nitric Oxide in the Inhibitory Effect of [d-Pen²,d-Pen⁵]-Enkephalin on Ascending Dorsal Horn Neurons in Normal and Diabetic Rats

Epidural lornoxicam administration – innocent

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Spinal Antinociceptive Effect of Epidural Nonsteroidal Antiinflammatory Drugs on Nitric Oxide-induced Hyperalgesia in Rats

Cited by 24 publications

References 39 publications

Flexibilide Obtained from Cultured Soft Coral Has Anti-Neuroinflammatory and Analgesic Effects through the Upregulation of Spinal Transforming Growth Factor-β1 in Neuropathic Rats

Flexibilide Obtained from Cultured Soft Coral Has Anti-Neuroinflammatory and Analgesic Effects through the Upregulation of Spinal Transforming Growth Factor-β1 in Neuropathic Rats

Role of Spinal Nitric Oxide in the Inhibitory Effect of [d-Pen2,d-Pen5]-Enkephalin on Ascending Dorsal Horn Neurons in Normal and Diabetic Rats

Epidural lornoxicam administration – innocent

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Role of Spinal Nitric Oxide in the Inhibitory Effect of [d-Pen²,d-Pen⁵]-Enkephalin on Ascending Dorsal Horn Neurons in Normal and Diabetic Rats