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Regulation of spinal substance p release by intrathecal calcium channel blockade

Toshifumi Takasusuki1, Tony L Yaksh

  • 1Department of Anesthesiology, School of Medicine, Dokkyo Medical University, Mibu, Tochigi, Japan.

Anesthesiology
|May 18, 2011
PubMed
Abstract

Insights

N-type calcium channel blockers reduced substance P release and nociception. T- and L-type blockers showed antihyperalgesic effects through different mechanisms, not involving substance P release.

Area of Science:

  • Neuroscience
  • Pharmacology

Background:

  • Voltage-sensitive calcium channels (VSCCs) are crucial for neurotransmitter release at presynaptic terminals.
  • Substance P release from small primary afferents mediates nociception.
  • Different VSCC subtypes (N, T, L-type) may play distinct roles in pain pathways.

Purpose of the Study:

  • To investigate the role of N-, T-, and L-type VSCCs in substance P release and formalin-induced nociceptive behavior.
  • To determine the specific contribution of each VSCC subtype to pain modulation.

Main Methods:

  • Rats received intrathecal administration of VSCC blockers (ziconotide, mibefradil, diltiazem, verapamil) or morphine.
  • Nociceptive behavior (paw flinching) was quantified after intraplantar formalin injection.
  • Substance P release was assessed by measuring neurokinin-1 receptor internalization in the spinal cord.

Main Results:

  • N-type VSCC blocker (ziconotide) and morphine reduced paw flinching and neurokinin-1 receptor internalization.
  • T- and L-type VSCC blockers (mibefradil, diltiazem, verapamil) reduced paw flinching but did not affect neurokinin-1 receptor internalization.
  • Antihyperalgesic effects of T- and L-type blockers were observed in phase 2 of the formalin test.

Conclusions:

  • N-type VSCCs are critical for stimulus-evoked substance P release from primary afferents in vivo.
  • T- and L-type VSCC blockers likely exert antihyperalgesic effects via mechanisms independent of substance P release, possibly involving postsynaptic excitability.

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