Heme oxygenase type 2 modulates behavioral and molecular changes during chronic exposure to morphine.
The heme oxygenase (HO) enzyme system has been shown to participate in nociceptive signaling in a number of different models of pain. In these experiments we investigated the role of the HO type 2 (HO-2) isozyme in tolerance to the analgesic effects of morphine, and the hyperalgesia and allodynia which are measurable upon cessation of administration. Wild type C57Bl/6 wild type mice or HO-2 null mutants in that background strain were treated with morphine for 5 days. The morphine administration protocol consisted of either twice daily repeated s.c. boluses of 15 mg/kg or s.c. implantation of a morphine pellet. At the end of the treatment period wild type mice treated by either protocol exhibited tolerance, but the HO-2 null mutants did not. The HO-2 null mutants also exhibited less mechanical allodynia following cessation of morphine administration, though only modest differences in thermal hyperalgesia were noted. There was no correlation between the degree of tolerance obtained in the bolus and pellet protocols and the degree of hyperalgesia and allodynia observed after cessation of morphine administration in the wild type mice. Our final experiments analyzed increases in expression of mRNA for nitric oxide synthase type 1, N-methyl-D-aspartate (NMDA) receptor NMDAR1 subunit and prodynorphin in spinal cord tissue. In pellet-treated mice two- to three-fold increases were observed in the abundance of these species, but very little change was observed in the null-mutant mice. Taken together our results indicate that HO-2 participates in the acquisition of opioid tolerance, the expression of mechanical allodynia after cessation of opioid administration and in gene regulation occurring in the setting of treatment with morphine. Furthermore, these studies suggest that the mechanisms underlying analgesic tolerance and opioid-induced hypersensitivity are at least somewhat distinct.
Veterans Affairs Palo Alto Health Care System and Stanford University Department of Anesthesiology, 3801 Miranda Avenue, Palo Alto, CA 94304, USA.
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D000818:Animals; D004334:Drug Administration Schedule; D004361:Drug Tolerance / Q000502:physiology*; D004745:Enkephalins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006419:Heme Oxygenase (Decyclizing) / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006930:Hyperalgesia / Q000188:drug therapy / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000235:genetics; D052248:Nitric Oxide Synthase Type I; D010146:Pain / Q000188:drug therapy / Q000201:enzymology*; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology*
D004745:Enkephalins; D006419:Heme Oxygenase (Decyclizing); D009020:Morphine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D011498:Protein Precursors; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C033660:preproenkephalin; C496321:Nos1 protein, mouse; C105245:heme oxygenase-2