The role of heme oxygenase in neuropathic and incisional pain.
Heme oxygenase (HO) catalyzes the formation of free iron, biliverdin, and the second messenger molecule carbon monoxide from heme. We document a role for HO in both neuropathic and incisional pain models. For our neuropathic model, the L5 and L6 nerve roots of rats were ligated unilaterally resulting in mechanical allodynia and thermal hyperalgesia in the ipsilateral hind paws. Both changes were dose-dependently reversed by systemic administration of the HO inhibitor tin protoporphyrin (Sn-P). Likewise, a 1-cm incision made in one hind paw resulted in mechanical allodynia and thermal hyperalgesia, again reversible by using Sn-P. The 50% effective doses for Sn-P ranged from 4.0 to 6.8 micromol/kg depending on the model and nociceptive stimulus. We also observed that the blood-brain barrier impermeable HO inhibitor zinc protoporphyrin had little analgesic activity in these models when injected systemically. Using an enzymatic assay, we observed increased HO activity in lumbar spinal cord tissue from either nerve root ligated or incised animals as compared with tissue from sham-operated animals. Taken together, we interpret our results to indicate that an increase in spinal cord HO activity at least partially underlies the allodynia and hyperalgesia seen in rat models of neuropathic and incisional pain.


CONCLUSIONS
Central nervous system heme oxygenase likely plays a role in nociceptive signaling in both neuropathic and incisional models of pain. Therefore, inhibitors of heme oxygenase activity may be viable analgesics in these settings.
Li
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Department of Anesthesiology, Stanford University and Veterans' Affairs Palo Alto Health Care Services, Palo Alto, California 94304, USA.
Clark
J D
JD
D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000502:physiology*; D006930:Hyperalgesia / Q000209:etiology; D008297:Male; D010146:Pain / Q000188:drug therapy / Q000209:etiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000700:Analgesics; D004791:Enzyme Inhibitors; D006419:Heme Oxygenase (Decyclizing)