Different effects of two aldose reductase inhibitors on nociception and prostaglandin E.
This study examined the effect of two structurally dissimilar aldose reductase inhibitors, N-[[5-(trifluoromethyl)-6-methoxy-1- napthalenyl]thioxomethyl]-N-methlyglycine (tolrestat) and 4-amino-2,6-dimethylphenyl-sulphonyl nitromethane (ICI 222155), on formalin-evoked behavioural responses in control and diabetic rats and on capsaicin-evoked release of prostaglandin E from spinal cord slices in vitro. Both compounds, given orally for 4 weeks, prevented hyperalgesia in diabetic rats 5-20 min after hindpaw formalin injection. ICI 222155 also prevented hyperalgesia in diabetic rats 21-60 min after formalin, whereas tolrestat suppressed activity in diabetic rats below controls and also suppressed activity in controls when given orally or intrathecally. Capsaicin-evoked release of prostaglandin E from spinal cord slices of control rats was significantly reduced by tolrestat, but not ICI 222155. These data suggest that hyperalgesia in diabetic rats is related to glucose metabolism by aldose reductase, whereas tolrestat has specific effects on formalin-evoked nociception associated with an ability to reduce spinal prostaglandin release.
Calcutt
N A
NA
Department of Pathology, University of California at San Diego, La Jolla 92093-0612, USA.
Li
L
L
Yaksh
T L
TL
Malmberg
A B
AB
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005260:Female; D005557:Formaldehyde; D006930:Hyperalgesia / Q000517:prevention & control; D007278:Injections, Spinal; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology; D009595:Nitroparaffins / Q000008:administration & dosage / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects; D011458:Prostaglandins E / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology
D009281:Naphthalenes; D009595:Nitroparaffins; D011458:Prostaglandins E; D013450:Sulfones; C040550:tolrestat; C097934:ICI 222155; D005557:Formaldehyde; D000449:Aldehyde Reductase