Additive Effects of Environmental Enrichment and Ketamine on Neuropathic Pain Relief by Reducing Glutamatergic Activation in Spinal Cord Injury in Rats.

W L Tai,E A Joosten,C W Cheung,L Sun,H Li,P Gu

doi:10.3389/fnins.2021.635187

Abstract

Spinal cord injury (SCI) impairs mobility and often results in complications like intractable neuropathic pain. A multi-approach management of this chronic pain condition has been encouraged, but little has been explored of the field. Here, we focus on the effect and underlying mechanism of environmental enrichment (EE), which promotes voluntary social and physical activities, combined with a clinical analgesic, ketamine, on SCI-induced neuropathic pain as well as motor dysfunction. We performed T13 spinal hemisection in rats, which induced unilateral motor impairment and neuropathic pain-like behaviors in the hindlimb. Treatment regimen started a week after SCI, which consists of ketamine administration (30 mg kg–1 day–1; intramuscular) for 10 days, or EE housing for 20 days, or their combination. Paw withdrawal response to mechanical and thermal stimuli, motor function, burrowing behaviors, and body weight was monitored. Spinal segments at T13 lesion and L4–L6 were collected for histopathological and protein analyses. The joint treatment of EE and ketamine provided greater relief of pain-like behaviors and locomotor recovery than did either paradigm alone. These improvements were associated with reduced cavitation area, astrogliosis, and perilesional phosphorylation of glutamate N-methyl-D-aspartate receptor (NMDAR). Concurrently, lumbar spinal analysis of NMDAR-linked excitatory markers in hypersensitization showed reduced activation of NMDAR, mitogen-activated protein kinase (MAPK) family, nuclear factor (NF)-κB, interleukin (IL)-1β signaling, and restored excitatory amino acid transporter 2 level. Our data support a better therapeutic efficacy of the combination, EE, and ketamine, in the attenuation of neuropathic pain and motor recovery by reducing spinal glutamatergic activation, signifying a potential multifaceted neurorehabilitation strategy to improve SCI patient outcome.

Highlights

Chronic neuropathic pain develops in approximately 65% of people following spinal cord injury (SCI), severely compromising patient’s life on top of motor impairment (Siddall et al, 2003; Duenas et al, 2016)
The current study aimed to investigate the efficacy of combination of EE and ketamine in attenuating SCI-induced neuropathic pain and motor defects as well as on NR2BNMDAR activity
Rats developed mechanical allodynia after SCI that persisted for at least 28 days, which was demonstrated by significantly lower paw withdrawal threshold (PWT) in the ipsilateral hindpaws of SCI rats than that in sham

Summary

Introduction

Chronic neuropathic pain develops in approximately 65% of people following spinal cord injury (SCI), severely compromising patient’s life on top of motor impairment (Siddall et al, 2003; Duenas et al, 2016). Environmental enrichment (EE) is a preclinical model of rehabilitation that facilitates voluntary motor, sensory, and cognition activities by provision of a stimulating environment, avoiding the risk of exercise overload. It is well-documented to enhance neurogenesis and locomotion, enabling its translational use in neurorehabilitation unit (Janssen et al, 2012; Tai et al, 2018b), but its role in post-SCI recovery remains largely unknown. EE has been proven beneficial in attenuating allodynia and hyperalgesia in both neuropathic and inflammatory pain models (Gabriel et al, 2009; Stagg et al, 2011) Such analgesic effects remain partial (Berrocal et al, 2007; Koopmans et al, 2012). Studies of traumatic brain injury have suggested that combination of EE with selective pharmacotherapies can confer added benefits (de la Tremblaye et al, 2019)

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