Latent Sensitization: A Model for Stress‐Sensitive Chronic Pain

Juan Carlos Marvizon1, Wendy Walwyn2, Ani Minasyan2, Wenling Chen1, Bradley K. Taylor3

1 Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, California, 2 Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, 3 Department of Physiology, School of Medicine, University of Kentucky Medical Center, Lexington, Kentucky
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 9.50
DOI:  10.1002/0471142301.ns0950s71
Online Posting Date:  April, 2015
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Abstract

Latent sensitization is a rodent model of chronic pain that reproduces both its episodic nature and its sensitivity to stress. It is triggered by a wide variety of injuries ranging from injection of inflammatory agents to nerve damage. It follows a characteristic time course in which a hyperalgesic phase is followed by a phase of remission. The hyperalgesic phase lasts between a few days to several months, depending on the triggering injury. Injection of μ‐opioid receptor inverse agonists (e.g., naloxone or naltrexone) during the remission phase induces reinstatement of hyperalgesia. This indicates that the remission phase does not represent a return to the normal state, but rather an altered state in which hyperalgesia is masked by constitutive activity of opioid receptors. Importantly, stress also triggers reinstatement. Here we describe in detail procedures for inducing and following latent sensitization in its different phases in rats and mice. © 2015 by John Wiley & Sons, Inc.

Keywords: chronic pain; constitutive activity; hyperalgesia; latent sensitization; neuropathic pain; opioid receptor; stress

     
 
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Table of Contents

  • Introduction
  • Basic Protocol 1: Complete Freund's Adjuvant–Induced Latent Sensitization in Mice
  • Alternate Protocol 1: Complete Freund's Adjuvant‐Induced Latent Sensitization in Rats
  • Support Protocol 1: Up‐and‐Down Method of von Frey Measurements
  • Commentary
  • Literature Cited
  • Figures
  • Tables
     
 
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Materials

Basic Protocol 1: Complete Freund's Adjuvant–Induced Latent Sensitization in Mice

  Materials
  • 6‐week‐old to 5‐month‐old female or male mice, 20 g and 24 g, respectively (e.g., C57Bl/6 J, Jax Mice, The Jackson Laboratory), five to eight mice per group per gender
  • PicoLab Rodent Diet 20 (LabDiet, cat. no. 5053) and water bottles
  • Complete Freund's adjuvant (CFA; Sigma, cat. no. F5881)
  • Naltrexone hydrochloride (Sigma, cat. no. N3136) or naloxone hydrochloride dihydrate (Sigma, cat. no. N7758)
  • Phosphate‐buffered saline (PBS; e.g., see appendix 2A)
  • Water, sterile
  • Isoflurane (Phoenix)
  • ∼30 cm × 15–cm polycarbonate mouse cages for up to five mice per cage
  • Animal room with control of light (30 to 50 Lux), ambient temperature (18° to 26°C), and relative humidity (30% to 70%)
  • von Frey filaments (see protocol 3Support Protocol)
  • 10.16 × 10.16–cm opaque acrylic enclosures on top of an elevated mesh metal grid with stand (IITC, CA, Part number 410), large enough to test multiple mice (Fig.  )
  • 50‐μl Hamilton syringe (Hamilton, cat. no. 7637‐01) with 30‐G needle.
  • Vaporizer for isoflurane, with induction box (Summit Anesthesia Support)
  • Additional reagents and equipment for measuring PWTs with von Frey filaments ( protocol 3Support Protocol) and for anesthetizing ( appendix 4B; Davis, ) and euthanizing ( appendix 4H; Donovan and Brown, ) mice

Alternate Protocol 1: Complete Freund's Adjuvant‐Induced Latent Sensitization in Rats

  Materials List
  • 250‐ to 300‐g male Sprague‐Dawley rats (Harlan), five to eight rats per group per gender, typically three per cage
  • Rat chow (e.g., LabDiet) and water bottles
  • Complete Freund's adjuvant (CFA; Sigma, cat. no. F5881)
  • Naltrexone hydrochloride (Sigma, cat. no.) N3136 or naloxone hydrochloride dihydrate (Sigma, cat. no, N7758)
  • 0.9% (w/v) saline, sterile
  • Water, sterile
  • Isoflurane (Phoenix)
  • Pentobarbital (e.g., Fatal‐Plus, Vortech Pharmaceuticals)
  • ∼20 × 33–cm polycarbonate rat cages
  • Animal room with control of light (30 to 50 Lux), ambient temperature, and relative humidity
  • 10.16 × 20.3–cm opaque acrylic enclosures on top of an elevated mesh metal grid with stand (IITC, part no. 410) large enough to test multiple mice
  • 50‐μl Hamilton syringe, 26‐G needle
  • Vaporizer for isoflurane, with induction box (Patterson Scientific)
  • Additional reagents and equipment for measuring baseline paw withdrawal thresholds (PWTs) with von Frey filaments ( protocol 3Support Protocol) and anesthetizing ( appendix 4B; Davis, ) and euthanizing rats ( appendix 4H; Donovan and Brown, )

Support Protocol 1: Up‐and‐Down Method of von Frey Measurements

  Materials
  • Treated mice ( protocol 1Basic Protocol) or rats ( protocol 3Alternate Protocol)
  • Set of eight von Frey filaments
    • For mice (Touch‐test; North Coast Medical): Log 10 [10*force (mg)] or (g) = 1.65 (0.008 g), 2.36 (0.02 g), 2.83 (0.07 g), 3.22 (0.61 g), 3.61 (0.4 g), 4.08 (1.0 g), 4.31 (2.0 g), 4.74 (6.0 g) or
    • For rats (Touch‐test; North Coast Medical): Log 10 [10*force (mg)] = 3.61 (0.4 g), 3.84 (0.6 g), 4.08 (1.0 g), 4.31 (2.0 g), 4.56 (4.0 g), 4.74 (6.0 g), 4.93 (8.0 g), 5.18 (15.0 g)
  • In‐house up‐and‐down scoring sheet (e.g., see Fig.  )
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Figures

Videos

Literature Cited

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