Enhancement of cutaneous nerve regeneration by 4-methylcatechol in resiniferatoxin-induced neuropathy

J Neuropathol Exp Neurol. 2008 Feb;67(2):93-104. doi: 10.1097/nen.0b013e3181630bb8.

Abstract

To generate an experimental neuropathy model in which small-diameter sensory nerves are specifically affected and to test a potential treatment, adult mice were given a single injection (50 microg/kg, i.p.) of the capsaicin analog resiniferatoxin (RTX). On Day 7 after RTX treatment, there was a 53% reduction in unmyelinated nerve density in the medial plantar nerve (p = 0.0067) and a 66% reduction in epidermal nerve density of hind paw skin (p = 0.0004) compared with vehicle-treated controls. Substance P-immunoreactive dorsal root ganglion neurons were also markedly depleted (p = 0.0001). These effects were associated with the functional deficit of prolonged withdrawal latencies to heat stimuli (p = 0.0007) on a hot plate test. The potential therapeutic effects of 4-methylcatechol (4MC) on this neuropathy were then tested by daily injections of 4MC (10 microg/kg, i.p.) from Days 7 to 35 after neuropathy induction. On Day 35, 4MC-treated mice had an increase in unmyelinated (p = 0.014) and epidermal nerve (p = 0.0013) densities and a reduction in thermal withdrawal latency (p = 0.0091) compared with RTX-only controls. These results indicate that 4MC promoted regeneration of unmyelinated nerves in experimental RTX-induced neuropathy and enhanced function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / metabolism
  • Capsaicin
  • Catechols / therapeutic use*
  • Disease Models, Animal
  • Diterpenes*
  • Drug Interactions
  • Ganglia, Spinal / metabolism
  • Hyperalgesia / drug therapy
  • Male
  • Mice
  • Mice, Inbred ICR
  • Nerve Fibers, Unmyelinated / drug effects
  • Nerve Fibers, Unmyelinated / pathology
  • Nerve Fibers, Unmyelinated / ultrastructure
  • Nerve Regeneration / drug effects*
  • Nerve Regeneration / physiology
  • Neural Conduction / drug effects
  • Neuroprotective Agents / therapeutic use*
  • Peripheral Nervous System Diseases* / chemically induced
  • Peripheral Nervous System Diseases* / drug therapy
  • Peripheral Nervous System Diseases* / physiopathology
  • Reaction Time / drug effects
  • Skin / innervation*
  • Substance P / metabolism
  • Ubiquitin Thiolesterase / metabolism

Substances

  • Catechols
  • Diterpenes
  • Neuroprotective Agents
  • 4-methylcatechol
  • Substance P
  • resiniferatoxin
  • Ubiquitin Thiolesterase
  • Uchl1 protein, mouse
  • Calcitonin Gene-Related Peptide
  • Capsaicin