Journal
NEUROSCIENCE
Volume 145, Issue 2, Pages 676-685Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2006.12.016
Keywords
nociceptors; analgesia; dorsal root ganglia; opioids; receptor binding; pain
Categories
Funding
- NCI NIH HHS [P30 CA016672, CA16672] Funding Source: Medline
- NIGMS NIH HHS [R01 GM064830, GM64830] Funding Source: Medline
- NINDS NIH HHS [R01 NS045602, NS45602] Funding Source: Medline
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Deletion of transient receptor potential vanilloid type 1 (TRPV1)-expressing afferent neurons reduces presynaptic p opioid receptors but paradoxically potentiates the analgesic efficacy of mu opioid agonists. In this study, we determined if removal of TRPV1-expressing afferent neurons by resiniferatoxin (RTX), an ultrapotent capsaicin analog, influences the development of opioid analgesic tolerance. Morphine tolerance was induced by daily intrathecal injections of 10 mu g of morphine for 14 consecutive days or by daily i.p. injections of 10 mg/kg of morphine for 10 days. In vehicle-treated rats, the effect of intrathecal or systemic morphine on the mechanical withdrawal threshold was gradually diminished within 7 days. However, the analgesic effect of intrathecal and systemic morphine was sustained in RTX-treated rats at the time the morphine effect was lost in the vehicle group. Furthermore, the mu opioid receptor-G protein coupling in the spinal cord was significantly decreased (similar to 22%) in vehicle-treated morphine tolerant rats, but was not significantly altered in RTX-treated rats receiving the same treatment with morphine. Additionally, there was a large reduction in protein kinase C gamma-immunoreactive afferent terminals in the spinal dorsal horn of RTX-treated rats. These findings suggest that loss of TRPV1-expressing sensory neurons attenuates the development of morphine analgesic tolerance possibly by reducing mu opioid receptor desensitization through protein kinase C gamma in the spinal cord. These data also suggest that the function of presynaptic mu opioid receptors on TRPV1-expressing sensory neurons is particularly sensitive to down-regulation by mu opioid agonists during opioid tolerance development. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.
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