Abstract
Studies have shown that long-term (5α,6α)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol (morphine) treatment increases the sensitivity to painful heat stimuli (thermal hyperalgesia). The cellular adaptations contributing to sustained morphine-mediated pain sensitization are not fully understood. It was shown previously (J Neurosci 22:6747–6755, 2002) that sustained morphine exposure augments pain neurotransmitter [such as calcitonin gene-related peptide (CGRP)] release in the dorsal horn of the spinal cord in response to the heat-sensing transient receptor potential vanilloid 1 receptor agonist 8-methyl-N-vanillyl-6-nonenamide (capsaicin). In the present study, we demonstrate that sustained morphine-mediated augmentation of CGRP release from isolated primary sensory dorsal root ganglion neurons is dependent on protein kinase A and Raf-1 kinase. Our data indicate that, in addition to neural system adaptations, sustained opioid agonist treatment also produces intracellular compensatory adaptations in primary sensory neurons, leading to augmentation of evoked pain neurotransmitter release from these cells.
Footnotes
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This work was supported in part by the National Institutes of Health National Institute on Drug Abuse [Grant DA06284]; and the National Institutes of Health National Institute of General Medical Sciences [Grant GM065465].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.109.151704.
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ABBREVIATIONS: TRPV, transient receptor potential vanilloid; CGRP, calcitonin gene-related peptide; PKA, protein kinase A; DRG, dorsal root ganglion; CHO, Chinese hamster ovary; SNC 80, (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide; AC, adenylyl cyclase; LG, l-glutamine; PS, penicillin-streptomycin; NGF, nerve growth factor; PBS, phosphate-buffered saline; DPN, diprenorphine; NTX, naltrexone; GW5074 (GW), 3-(3,5-dibromo-4-hydroxybenzylidene-5-iodo-1,3-dihydro-indol-2-one; H-89, N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinoline sulfonamide, 2HCl; PKI, myristoylated protein kinase A inhibitor 14-22 amide; Mor, morphine; ANOVA, analysis of variance; Cap, capsaicin; MAPK, mitogen-activated protein kinase; B27, 0.1 μg/ml biotin, 2.0 μg/ml l-carnitine, 15 μg/ml d-(+)-galactose, 1 μg/ml ethanolamine, 16.1 μg/ml putrescine, 0.016 μg/ml selenium, 0.02 μg/ml corticosterone, 1 μg/ml linoleic acid, 0.0063 μg/ml progesterone, 0.1 μg/ml retinyl acetate, 1 μg/ml dl-α-tocopherol, 1 μg/ml dl-α-tocopherol acetate, 2.5 μg/ml catalase, 4 μg/ml insulin, 2.5 μg/ml superoxide dismutase, 5 μg/ml human transferrin, 2.5 mg/ml albumin, 1 μg/ml reduced glutathione, 0.002 μg/ml triiodo-l-thyrosine.
- Received January 31, 2009.
- Accepted May 11, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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