A role for protein kinase C-dependent upregulation of adrenomedullin in the development of morphine tolerance in male rats.
Adrenomedullin (AM) belongs to calcitonin gene-related peptide (CGRP) family and is a pronociceptive mediator. This study investigated whether AM plays a role in the development of tolerance to morphine-induced analgesia. Repetitive intrathecal injection of morphine increased the expression of AM-like immunoreactivity (AM-IR) in the spinal dorsal horn and dorsal root ganglion (DRG) neurons. Ganglion explant culture study showed that this upregulation of AM-IR was μ-opioid receptor dependent through the use of another agonist, fentanyl, and a selective antagonist, CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2)). The coadministration of the selective AM receptor antagonist AM(22-52) markedly attenuated the development of morphine tolerance, associated thermal hyperalgesia, and increase in AM-IR. A likely autocrine mechanism is supported by the finding that AM-IR is colocalized with AM receptor components in DRG neurons. Furthermore, opiate-induced increase in AM content was blocked by protein kinase C (PKC) inhibitors, whereas a PKC activator increased AM synthesis and release. A treatment with AM(22-52) also inhibited increases in the expression of CGRP-IR in the spinal cord and DRGs as well as in culture ganglion explants, whereas exposure to CGRP failed to alter AM content. Together, these results reveal that a sustained opiate treatment induces an upregulation of AM through the activation of μ-opioid receptors and the PKC signaling pathway. This phenomenon contributes to the development of tolerance to the antinociceptive effects of opiates at least partially via the upregulation of CGRP. Targeting AM and its receptors should be considered as a novel approach to preserve the analgesic potency of opiates during their chronic use.
Hong
Yanguo
Y
Provincial Key Laboratory of Developmental Biology and Neuroscience, Fujian Normal University, Fuzhou, Fujian 350108, People's Republic of China.
Wang
Dongmei
D
Chabot
Jean-Guy
JG
Ma
Weiya
W
Chen
Peiwen
P
Quirion
Rémi
R
D053607:Adrenomedullin / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D058286:Calcitonin Receptor-Like Protein; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004361:Drug Tolerance / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D009294:Narcotics / Q000008:administration & dosage; D009924:Organ Culture Techniques; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin / Q000378:metabolism; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D000701:Analgesics, Opioid; D058286:Calcitonin Receptor-Like Protein; D009294:Narcotics; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin; D018000:Receptors, Peptide; D053607:Adrenomedullin; D009020:Morphine; D011493:Protein Kinase C