Korean J Anesthesiol.  2005 Jan;48(1):76-84. 10.4097/kjae.2005.48.1.76.

The Role of Nitric Oxide Synthase Isoforms in Neuropathic Pain Induced by Nerve Injury in Rats

• Jeon YT
• Seo KS
• Ro YJ
• Lim YJ
• Min SW
• Kim YC
• Kim CS
• Lee SC
• Kim SD

• KMID: 2091959
• DOI: http://doi.org/10.4097/kjae.2005.48.1.76

Abstract

BACKGROUND: Peripheral nerve injury may generate pain hypersensitivity, characterized by enhanced nociceptive responses to noxious stimuli and decreased thresholds to innocuous stimuli, and may lead to a chronic neuropathic pain state resulting from an increase in central neuron excitability. This central sensitization is mediated via N-methyl-D-aspartic acid (NMDA) receptor and may involve the production of nitric oxide (NO). In this work, we investigated whether the action of NO and local nitric oxide synthase (NOS) expression play a role in neuropathic pain in a rat model.
METHODS
Neuropathic pain was produced by resecting two branches of the sciatic nerve. N-nitro-L-arginine methyl ester (L-NAME) (a nonselective NOS inhibitor), or 7-nitroindazole (7-NI) (a neuronal NOS (nNOS) inhibitor), or aminoguanidine (AG) (an inducible NOS (iNOS) inhibitor) were administered locally for 2, 7, or 14 days via osmotic pumps. Behavioral tests for pain were conducted after nerve injury using mechanical and thermal stimuli applied to the hind paws. We used immunohistochemical methods to provide evidence for endothelial NOS (eNOS), nNOS, and iNOS expression.
RESULTS
Following nerve injury, significant mechanical allodynia and thermal hyperalgesia were observed in rats treated with AG or 7-NI. In contrast, when L-NAME, a known potent inhibitor of eNOS was applied locally, no significant mechanical allodynia or thermal hyperalgesia was observed. No dependency on the route or duration of NOS inhibitor administration was noted. Increased immunoreactivities of the eNOS and nNOS isoforms were intense and discrete at 48 hour following nerve injury, unlike sham exposed intact nerves. In 14 day stumps, iNOS staining was observed in the endoneurium and perineurium. eNOS immunoreactivity at 2 days after nerve injury was not observed in L-NAME treated rats. At 14 days after nerve injury, iNOS immunoreactivity was rarely observed in AG and L-NAME treated rats.
CONCLUSIONS
Our results indicate that an early eNOS expression plays a critical role in the development of neuropathic pain.

Keyword

allodynia; hyperalgesia; nitric oxide; nitric oxide synthase; neuropathic pain

MeSH Terms

Animals
Central Nervous System Sensitization
Hyperalgesia
Hypersensitivity
Models, Animal
N-Methylaspartate
Neuralgia*
Neurons
NG-Nitroarginine Methyl Ester
Nitric Oxide Synthase*
Nitric Oxide*
Peripheral Nerve Injuries
Peripheral Nerves
Protein Isoforms
Rats*
Sciatic Nerve
N-Methylaspartate
NG-Nitroarginine Methyl Ester
Nitric Oxide
Nitric Oxide Synthase
Protein Isoforms