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Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
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Resistance to morphine analgesic tolerance in rats with deleted transient receptor potential vanilloid type

S-R Chen1, A Prunean, H-M Pan

  • 1Department of Anesthesiology and Pain Medicine, Unit 409, The University of Texas M. D. Anderson Cancer Center, 1400 Holcombe Boulevard, Houston, TX 77030-4009, USA.

Neuroscience
|January 24, 2007
PubMed

Insights

Removing TRPV1-expressing neurons with resiniferatoxin (RTX) prevents morphine analgesic tolerance. This suggests TRPV1 neurons are key in opioid tolerance development, offering new therapeutic targets.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Pain Research

Background:

  • Transient receptor potential vanilloid type 1 (TRPV1)-expressing afferent neurons play a complex role in pain signaling and opioid receptor function.
  • Opioid analgesic tolerance, a decrease in drug efficacy over time, is a significant clinical challenge.
  • Presynaptic mu opioid receptors on TRPV1 neurons are implicated in modulating pain perception.

Purpose of the Study:

  • To investigate whether the deletion of TRPV1-expressing afferent neurons affects the development of morphine analgesic tolerance.
  • To determine the impact of TRPV1 neuron ablation on mu opioid receptor (MOR) signaling and desensitization during morphine treatment.

Main Methods:

  • Resiniferatoxin (RTX), a selective TRPV1-expressing neuron toxin, was used to ablate these neurons in rats.
  • Morphine tolerance was induced via intrathecal or intraperitoneal injections over 10-14 days.
  • Mechanical withdrawal thresholds were measured to assess analgesic effects.
  • Mu opioid receptor-G protein coupling and protein kinase Cgamma (PKCγ) expression in the spinal cord were analyzed.

Main Results:

  • Rats treated with RTX showed sustained analgesic effects from morphine, unlike vehicle-treated controls that developed tolerance.
  • Morphine-tolerant vehicle-treated rats exhibited a significant decrease in spinal MOR-G protein coupling (~22%).
  • RTX-treated rats receiving morphine did not show a significant reduction in MOR-G protein coupling.
  • A substantial reduction in PKCγ-immunoreactive afferent terminals was observed in the spinal dorsal horn of RTX-treated rats.

Conclusions:

  • Ablation of TRPV1-expressing afferent neurons attenuates the development of morphine analgesic tolerance.
  • This attenuation may be mediated by reduced MOR desensitization, potentially involving PKCγ in the spinal cord.
  • Presynaptic MORs on TRPV1-expressing sensory neurons are particularly susceptible to agonist-induced down-regulation during tolerance development.

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