Treatment of a chronic allodynia-like response in spinally injured rats: effects of systemically administered nitric oxide synthase inhibitors.
We have previously reported that we have observed chronic pain-like response to light mechanical stimuli (allodynia) in rats after severe spinal cord ischemia, which resembles some painful conditions in chronic spinally injured patients and is not relieved by a number of conventional analgesics used for treating chronic neuropathic pain. In the present study, we tested the effects of the non-selective nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and the selective neuronal NOS inhibitor 7-nitro indazole (7-NI) and 6-nitro indazole (6-NI) on the chronic allodynia-like behavior. Systemic L-NAME dose-dependently relieved mechanical allodynia-like response in a stereo-specific and L-arginine-reversible manner without causing sedation or motor deficits. However, L-NAME significantly elevated systemic blood pressure. Systemic 7-NI relieved chronic allodynia in a L-arginine reversible manner, did not increase blood pressure or induce sedation, but caused motor deficits at a high dose, which was not reversed by L-arginine. Systemic 6-NI also relieved the chronic allodynia, which was however associated with severe sedation. In order to exclude the possibility that the effect of L-NAME on blood pressure was involved in the analgesic effect observed, the effect of systemically applied adrenaline was examined. Adrenaline increased the systemic blood pressure to a similar extent as L-NAME, but did not relieve allodynia. It is suggested that blockade of NOS by L-NAME relieved the chronic allodynia-like behavior in spinally injured rats. This effect was likely to be mediated by a blockade of neuronal isoforms of NOS, as 7-NI relieved the allodynia in a L-arginine-reversible manner. Consequently, generation of NO by neuronal NOS may be critically involved in the maintenance of this abnormal pain-related sensation. The possibility of using NOS inhibitors as potential novel analgesics is discussed.
Hao
J X
JX
Karolinska Institute, Department of Medical Laboratory Sciences and Technology, Huddinge University Hospital, Sweden.
Xu
X J
XJ
D000322:Adrenergic Agonists / Q000097:blood / Q000494:pharmacology; D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004837:Epinephrine / Q000097:blood / Q000494:pharmacology; D005260:Female; D007191:Indazoles / Q000627:therapeutic use; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D010812:Physical Stimulation; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000150:complications* / Q000503:physiopathology
D000322:Adrenergic Agonists; D000700:Analgesics; D004791:Enzyme Inhibitors; D007191:Indazoles; C104292:6-nitroindazole; D019001:Nitric Oxide Synthase; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester; D004837:Epinephrine