Comparison of Burrowing and Stimuli-Evoked Pain Behaviors as End-Points in Rat Models of Inflammatory Pain and Peripheral Neuropathic Pain.

Arjun Muralidharan,Meera Jacob,Laura Corradini,Jacintha S Lourdesamy,Lara Melo Soares Pinho De Carvalho,Janet R Nicholson,Maree T Smith,Andy Kuo

doi:10.3389/fnbeh.2016.00088

Abstract

Establishment and validation of ethologically-relevant, non-evoked behavioral end-points as surrogate measures of spontaneous pain in rodent pain models has been proposed as a means to improve preclinical to clinical research translation in the pain field. Here, we compared the utility of burrowing behavior with hypersensitivity to applied mechanical stimuli for pain assessment in rat models of chronic inflammatory and peripheral neuropathic pain. Briefly, groups of male Sprague-Dawley rats were habituated to the burrowing environment and trained over a 5-day period. Rats that burrowed ≤ 450 g of gravel on any 2 days of the individual training phase were excluded from the study. The remaining rats received either a unilateral intraplantar injection of Freund's complete adjuvant (FCA) or saline, or underwent unilateral chronic constriction injury (CCI) of the sciatic nerve- or sham-surgery. Baseline burrowing behavior and evoked pain behaviors were assessed prior to model induction, and twice-weekly until study completion on day 14. For FCA- and CCI-rats, but not the corresponding groups of sham-rats, evoked mechanical hypersensitivity developed in a temporal manner in the ipsilateral hindpaws. Although burrowing behavior also decreased in a temporal manner for both FCA-and CCI- rats, there was considerable inter-animal variability. By contrast, mechanical hyperalgesia and mechanical allodynia in the ipsilateral hindpaws of FCA- and CCI-rats respectively, exhibited minimal inter-animal variability. Our data collectively show that burrowing behavior is altered in rodent models of chronic inflammatory pain and peripheral neuropathic pain. However, large group sizes are needed to ensure studies are adequately powered due to considerable inter-animal variability.

Highlights

Chronic pain, that affects ∼15–20% of the adult population globally (van Hecke et al, 2013), is underpinned by complex cellular and molecular pathophysiological mechanisms (Basbaum et al, 2009)
The timelines for assessments of burrowing behavior, mechanical hyperalgesia, hindpaw edema and/or mechanical allodynia in the Freund’s complete adjuvant (FCA)- and constriction injury (CCI)-rat models used in the present study, are summarized in Figures 1A,B, respectively
The general animal health, pain hypersensitivity behaviors, hindpaw volumes (FCA-rats only) and burrowing data from all rat cohorts are described

Summary

Introduction

That affects ∼15–20% of the adult population globally (van Hecke et al, 2013), is underpinned by complex cellular and molecular pathophysiological mechanisms (Basbaum et al, 2009). Rodent models of individual chronic pain conditions are crucial to improving our collective understanding of the specific pathobiological mechanisms and for screening new molecules as potential analgesic or adjuvant agents (Mogil et al, 2010). Most compounds that modulate these targets failed to show analgesic efficacy in proof-of-concept human clinical trials, despite promising preclinical data (Smith and Muralidharan, 2015). This perceived failure of drug candidates in clinical trials, has led to calls for the replacement of rodent pain models with studies in human volunteers (Langley et al, 2008)

Methods

Results

Conclusion