Amitriptyline suppresses neuroinflammation-dependent interleukin-10-p38 mitogen-activated protein kinase-heme oxygenase-1 signaling pathway in chronic morphine-infused rats.
BACKGROUND
This study explores the underlying mechanism of the antiinflammatory effect of amitriptyline in chronic morphine-infused rats.


METHODS
Male Wistar rats were implanted with two intrathecal catheters. One catheter was for the continuous infusion of saline, amitriptyline (15 microg/h), morphine (15 microg/h), p38 mitogen-activated protein kinase inhibitor SB203580 (0.5 microg/h), morphine plus amitriptyline, or morphine plus amitriptyline plus SB203580 for 5 days. The other catheter was used for daily intrathecal injection of anti-interleukin-10 (IL-10) antibody or heme oxygenase-1 inhibitor zinc protoporphyrin for 5 days.


RESULTS
Amitriptyline/morphine coinfusion upregulated IL-10 protein expression in microglia; this was not observed in morphine-infused rats. Anti-IL-10 antibody effectively neutralized the amitriptyline-induced IL-10 expression in chronic morphine-infused rats. In addition, coinfusion of amitriptyline restored the antinociceptive effect of morphine (a 4.8-fold right-shift of the morphine dose-response curve compared to a 77.8-fold right-shift in its absence), and the injection of anti-IL-10 antibody or coinfusion of SB203580 partially reversed the effect of amitriptyline on the antinociceptive effect of morphine in morphine-infused rats (a 17.9-fold and 15.1-fold right-shift in morphine dose-response curves). Anti-IL-10 antibody and SB203580 significantly inhibited the amitriptyline-induced p38 mitogen-activated protein kinase and heme oxygenase-1 expression and the associated antiinflammatory effect of amitriptyline. Daily injection of zinc protoporphyrin also demonstrated that it reverses the effect of amitriptyline in morphine's antinociception and antiinflammation in chronic morphine-infused rats.


CONCLUSIONS
These results suggest that the antiinflammatory effect of amitriptyline on morphine tolerance, probably acting by increasing IL-10 expression, is mediated by p38 mitogen-activated protein kinase heme oxygenase-1 signal transduction cascade.
Tai
Yueh-Hua
YH
Nociception Signal Transduction Laboratory, Department of Anesthesiology, Tri-Service General Hospital and the National Defense Medical Center, Taipei, Taiwan.
Tsai
Ru-Yin
RY
Lin
Shinn-Long
SL
Yeh
Chun-Chang
CC
Wang
Jhi-Joung
JJ
Tao
Pao-Luh
PL
Wong
Chih-Shung
CS
D000639:Amitriptyline / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D019138:Antibodies, Blocking / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009187:Myelitis / Q000201:enzymology* / Q000503:physiopathology*; D010147:Pain Measurement / Q000187:drug effects; D011524:Protoporphyrins / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019138:Antibodies, Blocking; D000929:Antidepressive Agents, Tricyclic; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011524:Protoporphyrins; D011725:Pyridines; D016753:Interleukin-10; C017803:zinc protoporphyrin; D000639:Amitriptyline; D009020:Morphine; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580