Fast-conducting mechanoreceptors contribute to withdrawal behavior in normal and nerve injured rats

Pain. 2014 Dec;155(12):2646-55. doi: 10.1016/j.pain.2014.09.030. Epub 2014 Sep 28.

Abstract

Fast-conducting myelinated high-threshold mechanoreceptors (AHTMR) are largely thought to transmit acute nociception from the periphery. However, their roles in normal withdrawal and in nerve injury-induced hyperalgesia are less well accepted. Modulation of this subpopulation of peripheral neurons would help define their roles in withdrawal behaviors. The optically active proton pump, ArchT, was placed in an adeno-associated virus-type 8 viral vector with the CAG promoter and was administered by intrathecal injection resulting in expression in myelinated neurons. Optical inhibition of peripheral neurons at the soma and transcutaneously was possible in the neurons expressing ArchT, but not in neurons from control animals. Receptive field characteristics and electrophysiology determined that inhibition was neuronal subtype-specific with only AHTMR neurons being inhibited. One week after nerve injury the AHTMR are hyperexcitable, but can still be inhibited at the soma and transcutaneously. Withdrawal thresholds to mechanical stimuli in normal and in hyperalgesic nerve-injured animals also were increased by transcutaneous light to the affected hindpaw. This suggests that AHTMR neurons play a role not only in threshold-related withdrawal behavior in the normal animal, but also in sensitized states after nerve injury. This is the first time this subpopulation of neurons has been reversibly modulated to test their contribution to withdrawal-related behaviors before and after nerve injury. This technique may prove useful to define the role of selective neuronal populations in different pain states.

Keywords: A fiber; C fiber; Electrophysiology; Hyperalgesia; Mechanotransduction; Nerve injury; Neuropathic; Nociceptor; Optogenetics; Pain; Sensory neuron; Withdrawal.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Dependovirus / genetics
  • Disease Models, Animal
  • Ganglia, Spinal / cytology
  • Glial Fibrillary Acidic Protein / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hyperalgesia / pathology
  • Hyperalgesia / physiopathology
  • Male
  • Mechanoreceptors / physiology*
  • Membrane Potentials / physiology
  • Nerve Fibers, Myelinated / physiology*
  • Neural Conduction / physiology*
  • Neurofilament Proteins / metabolism
  • Pain Measurement
  • Pain Threshold / physiology
  • Peripheral Nerve Injuries / pathology*
  • Peripheral Nerve Injuries / physiopathology*
  • Proton Pumps / genetics
  • Proton Pumps / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Transgenic
  • Time Factors

Substances

  • Glial Fibrillary Acidic Protein
  • Neurofilament Proteins
  • Proton Pumps
  • neurofilament protein H
  • Green Fluorescent Proteins