Inhibitors of catechol-O-methyltransferase sensitize mice to pain.
OBJECTIVE
Catechol-O-methyltransferase (COMT) inhibitors are used in Parkinson's disease in which pain is an important symptom. COMT polymorphisms modulate pain and opioid analgesia in humans. In rats, COMT inhibitors have been shown to be pro-nociceptive in acute pain models, but also to attenuate allodynia and hyperalgesia in a model of diabetic neuropathy. Here, we have assessed the effects of acute and repeated administrations of COMT inhibitors on mechanical, thermal and carrageenan-induced nociception in male mice.


METHODS
We used single and repeated administration of a peripherally restricted, short-acting (nitecapone) and also a centrally acting (3,5-dinitrocatechol, OR-486) COMT inhibitor. We also tested CGP 28014, an indirect inhibitor of COMT enzyme. Effects of OR-486 on thermal nociception were also studied in COMT deficient mice. Effects on spinal pathways were assessed in rats given intrathecal nitecapone.


RESULTS
After single administration, both nitecapone and OR-486 reduced mechanical nociceptive thresholds and thermal nociceptive latencies (hot plate test) at 2 and 3 h, regardless of their brain penetration. These effects were still present after chronic treatment with COMT inhibitors for 5 days. Intraplantar injection of carrageenan reduced nociceptive latencies and both COMT inhibitors potentiated this reduction without modifying inflammation. CGP 28014 shortened paw flick latencies. OR-486 did not modify hot plate times in Comt gene deficient mice. Intrathecal nitecapone modified neither thermal nor mechanical nociception.


CONCLUSIONS
Pro-nociceptive effects of COMT inhibitors were confirmed. The pro-nociceptive effects were primarily mediated via mechanisms acting outside the brain and spinal cord. COMT protein was required for these actions.
Kambur
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O
Primary laboratory of origin: Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland. oleg.kambur@helsinki.fi
Talka
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R
Ansah
O B
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Kontinen
V K
VK
Pertovaara
A
A
Kalso
E
E
Männistö
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PT
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000008:administration & dosage / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009619:Nociceptors / Q000502:physiology*; D010146:Pain / Q000139:chemically induced* / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D010422:Pentanones / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D010422:Pentanones; C057364:nitecapone; D002394:Catechol O-Methyltransferase; C057726:OR486