Sustained cannabinoid agonist treatment augments CGRP release in a PKA-dependent manner.
Studies have shown that sustained cannabinoid treatment increases the sensitivity to painful heat stimuli (thermal hyperalgesia) and innocuous mechanical stimuli (tactile allodynia). It has been suggested that augmented release of pain neurotransmitters (such as calcitonin gene-related peptide, CGRP) might be responsible for this abnormal pain sensitization. We hypothesize that intracellular adaptations upon sustained cannabinoid treatment causes augmented release of CGRP from primary nociceptors leading to increased pain sensitivity. We show that sustained (24 h) cannabinoid agonist [(+)WIN 55,212-2] treatment of 7-day-old neonatal rat dorsal root ganglion neurons significantly augments basal CGRP release from these cells in a protein kinase A-dependent manner. Our results indicate that these intracellular compensatory adaptations may play a crucial trigger role in further neuronal system adaptations for modulation of pain.
Tumati
Suneeta
S
Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA.
Yamamura
Henry I
HI
St John
Paul A
PA
Vanderah
Todd W
TW
Roeske
William R
WR
Varga
Eva V
EV
D000818:Animals; D000831:Animals, Newborn; D048588:Benzoxazines / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002186:Cannabinoids / Q000494:pharmacology*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004334:Drug Administration Schedule; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000378:metabolism / Q000503:physiopathology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology
D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D017868:Cyclic AMP-Dependent Protein Kinases; D015740:Calcitonin Gene-Related Peptide