Spinal Mobilization Prevents NGF-Induced Trunk Mechanical Hyperalgesia and Attenuates Expression of CGRP.

William R Reed,Joshua W Little,Christopher P Hurt,Peng Li,Daniel F Martins,Ceren Yarar-Fisher,Carla R Lima,Jianguo G Gu,Timothy J Ness,Mualla Eraslan,Robert E Sorge

doi:10.3389/fnins.2020.00385

Abstract

IntroductionLow back pain (LBP) is a complex and growing global health problem in need of more effective pain management strategies. Spinal mobilization (SM) is a non-pharmacological approach recommended by most clinical guidelines for LBP, but greater utilization and treatment optimization are hampered by a lack of mechanistic knowledge underlying its hypoalgesic clinical effects.MethodsGroups of female Sprague-Dawley rats received unilateral trunk (L5 vertebral level) injections (50 μl) of either vehicle (phosphate-buffer solution, PBS; VEH) or nerve growth factor (NGF; 0.8 μM) on Days 0 and 5 with or without daily L5 SM (VEH, NGF, VEH + SM, VEH + SM). Daily passive SM (10 min) was delivered by a feedback motor (1.2 Hz, 0.9N) from Days 1 to 12. Changes in pain assays were determined for mechanical and thermal reflexive behavior, exploratory behavior (open field events) and spontaneous pain behavior (rat grimace scale). On Day 12, lumbar (L1–L6) dorsal root ganglia (DRG) were harvested bilaterally and calcitonin gene-related peptide (CGRP) positive immunoreactive neurons were quantified from 3 animals (1 DRG tissue section per segmental level) per experimental group.ResultsNGF induced bilateral trunk (left P = 0.006, right P = 0.001) mechanical hyperalgesia and unilateral hindpaw allodynia (P = 0.006) compared to the vehicle group by Day 12. Additionally, we found for the first time that NGF animals demonstrated decreased exploratory behaviors (total distance traveled) and increased grimace scale scoring compared to the VEH group. Passive SM prevented this development of local (trunk) mechanical hyperalgesia and distant (hindpaw) allodynia, and normalized grimace scale scores. NGF increased CGRP positive immunoreactive neurons in ipsilateral lumbar DRGs compared to the VEH group ([L1]P = 0.02; [L2]P = 0.007) and SM effectively negated this increase in pain-related neuropeptide CGRP expression.ConclusionSM prevents the development of local (trunk) NGF-induced mechanical hyperalgesia and distant (hindpaw) allodynia, in part, through attenuation of CGRP expression in lumbar DRG sensory neurons. NGF decreases rat exploratory behavior and increases spontaneous pain for which passive SM acts to mitigate these pain-related behavioral changes. These initial study findings suggest that beginning daily SM soon after injury onset might act to minimize or prevent the development of LBP by reducing production of pain-related neuropeptides.

Highlights

Low back pain (LBP) is a complex and growing global health problem in need of more effective pain management strategies
In the current study we investigated whether passive spinal mobilization (SM) prevents the development of local mechanical hyperalgesia and distant allodynia in a nerve growth factor (NGF)-induced LBP model, as well as, if SM decreases the number of calcitonin gene-related peptide (CGRP)-positive lumbar dorsal root ganglia (DRG) neurons as a potential mechanism of action for any pain-related behavioral outcomes
We found that NGF trunk injections increased rat grimace scale (RGS) scoring throughout experimental testing, with significance achieved only during the early development of the persistent phase of LBP after the 2nd NGF injection but scores remained elevated throughout the entire study

Summary

Introduction

Low back pain (LBP) is a complex and growing global health problem in need of more effective pain management strategies. Mobilization has been reported to induce local and/or distant antihyperalgesic/analgesic effects in both preclinical models (Martins et al, 2012, 2013a,b; Santos et al, 2018; Salgado et al, 2019), and human studies (Vicenzino et al, 1996; La Touche et al, 2013; SalomMoreno et al, 2014) but mechanistic knowledge related to peripheral/central pain processing remains severely limited This gap in knowledge of specific anatomical structures, pathways, and molecular mechanisms responsible for SMinduced antihyperalgesia/analgesia is due in large part to a lack of adequate clinically relevant preclinical LBP models and non-reflex oriented behavioral assays in which to investigate LBP mechanisms and biological effects of pharmacological and nonpharmacological (active or passive) therapeutic interventions. LBP models that use minimally invasive techniques and/or endogeneously synthetized molecules may be preferable to some of the more invasive or traditional inflammatory LBP animal models (Shi et al, 2018)

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