Ca2+/calmodulin-dependent protein kinase II alpha is required for the initiation and maintenance of opioid-induced hyperalgesia.
Repeated administration of opioids not only leads to tolerance and dependence, but also results in nociceptive enhancement called opioid-induced hyperalgesia (OIH). Nociceptive mediators involved in OIH generation remain poorly understood. In the present study, we tested the hypothesis that Ca(2+)/calmodulin-depent protein kinase II (CaMKIIalpha) is critical for OIH. Opioid-induced hyperalgesia was produced by repeated morphine administration or pellet implantation in mice. Correlating with the development of tactile allodynia and thermal hyperalgesia, spinal CaMKIIalpha activity was significantly increased in OIH. KN93, a CaMKII inhibitor, dose- and time-dependently reversed OIH and CaMKII activation without impairing locomotor coordination. To elucidate the specific CaMKII isoform involved, we targeted CaMKIIalpha by using small interfering RNA and demonstrated that knockdown of spinal CaMKIIalpha attenuated OIH. Furthermore, morphine failed to induce OIH in CaMKIIalpha(T286A) point mutant mice, although wild-type littermate mice developed robust OIH after repeated treatments with morphine. These data implicate, for the first time, an essential role of CaMKIIalpha as a cellular mechanism leading to and maintaining opioid-induced hyperalgesia.
Chen
Yan
Y
Department of Biopharmaceutical Sciences, University of Illinois, Chicago, Illinois 60612, USA.
Yang
Cheng
C
Wang
Zaijie Jim
ZJ
D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology / Q000627:therapeutic use; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009020:Morphine / Q000633:toxicity; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010812:Physical Stimulation / Q000009:adverse effects; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D000096926:Benzenesulfonamides
D000701:Analgesics, Opioid; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D009020:Morphine; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides