Resistance to morphine analgesic tolerance in rats with deleted transient receptor potential vanilloid type 1-expressing sensory neurons

Abstract Deletion of transient receptor potential vanilloid type 1 (TRPV1)-expressing afferent neurons reduces presynaptic μ opioid receptors but paradoxically potentiates the analgesic efficacy of μ opioid agonists. In this study, we determined if removal of TRPV1-expressing afferent neurons by res...

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Veröffentlicht in:Neuroscience 2007-03, Vol.145 (2), p.676-685
Hauptverfasser: Chen, S.-R, Prunean, A, Pan, H.-M, Welker, K.L, Pan, H.-L
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Sprache:eng
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Zusammenfassung:Abstract Deletion of transient receptor potential vanilloid type 1 (TRPV1)-expressing afferent neurons reduces presynaptic μ opioid receptors but paradoxically potentiates the analgesic efficacy of μ 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 μg 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 μ opioid receptor-G protein coupling in the spinal cord was significantly decreased (∼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 Cγ-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 μ opioid receptor desensitization through protein kinase Cγ in the spinal cord. These data also suggest that the function of presynaptic μ opioid receptors on TRPV1-expressing sensory neurons is particularly sensitive to down-regulation by μ opioid agonists during opioid tolerance development.
ISSN:0306-4522
1873-7544
DOI:10.1016/j.neuroscience.2006.12.016