Unilateral T13 and L1 Dorsal Root Avulsion: Methods for a Novel Model of Central Neuropathic Pain

Wieseler, Julie; Ellis, Amanda; Maier, Steven F.; Watkins, Linda R.; Falci, Scott

doi:10.1007/978-1-61779-561-9_12

Cited by 4 publications

(3 citation statements)

References 20 publications

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“…Some models use complete deafferentation of the ipsilateral forepaw, [27][28][29][30] or a thoracic avulsion 31,57 to characterize bilateral pain in the hind paws. These two models do not represent avulsion pain as it is known in the clinic.…”

Section: Discussionmentioning

confidence: 99%

Segmental Spinal Root Avulsion in the Adult Rat: A Model To Study Avulsion Injury Pain

Chew

Murrell

Carlstedt

et al. 2013

Journal of Neurotrauma

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Road traffic accidents are the most common cause of avulsion injury, in which spinal roots are torn from the spinal cord. Patients suffer from a loss of sensorimotor function, intractable spontaneous pain, and border-zone hypersensitivity. The neuropathic pains are particularly difficult to treat because the lack of a well-established animal model of avulsion injury prevents identifying the underlying mechanisms and hinders the development of efficacious drugs. This article describes a hindlimb model of avulsion injury in adult rats where the L5 dorsal and ventral spinal root are unilaterally avulsed (spinal root avulsion [SRA]), leaving the adjacent L4 spinal root intact. SRA produced a significant ipsilateral hypersensitivity to mechanical and thermal stimulation by 5 days compared with sham-operated or naïve rats. This hypersensitivity is maintained for up to 60 days. No autotomy was observed and locomotor deficits were minimal. The hypersensitivity to peripheral stimuli could be temporarily ameliorated by administration of amitriptyline and carbamazepine, drugs that are currently prescribed to avulsion patients. Histological assessment of the L4 ganglion cells revealed no significant alterations in calcitonin gene-related peptide (CGRP), IB4, transient receptor potential cation channel subfamily V member 1 (TrpV1), or N52 staining across groups. Immunohistochemistry of the spinal cord revealed a localized glial response, phagocyte infiltration, and neuronal loss within the ipsilateral avulsed segment. A comparable response from glia and phagocytes was also found in the intact L4 spinal cord, supporting the role for central mechanisms within the L4-5 spinal cord in contributing to the generation of the pain-related behavior. The SRA model provides a platform to investigate possible new pharmacological treatments for avulsion injuries.

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Section: Discussionmentioning

confidence: 99%

Segmental Spinal Root Avulsion in the Adult Rat: A Model To Study Avulsion Injury Pain

Chew

Murrell

Carlstedt

et al. 2013

Journal of Neurotrauma

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“…Unilateral (left) T13 dorsal root avulsion was performed under isoflurane anesthesia, as previously described in detail (Wieseler et al, 2012). Briefly, laminectomy was performed at the T12 vertebral level and the dura mater was incised over the dorsal root entry zone.…”

Section: Methodsmentioning

confidence: 99%

Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury

Ellis

Grace

Wieseler

et al. 2016

Brain, Behavior, and Immunity

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Central neuropathic pain (CNP) is a pervasive, debilitating problem that impacts thousands of people living with central nervous system disorders, including spinal cord injury (SCI). Current therapies for treating this type of pain are ineffective and often have dose-limiting side effects. Although opioids are one of the most commonly used CNP treatments, recent animal literature has indicated that administering opioids shortly after a traumatic injury can actually have deleterious effects on long-term health and recovery. In order to study the deleterious effects of administering morphine shortly after trauma, we employed our low thoracic (T13) dorsal root avulsion model (Spinal Neuropathic Avulsion Pain, SNAP). Administering a weeklong course of 10 mg/kg/day morphine beginning 24 hr after SNAP resulted in amplified mechanical allodynia. Co-administering the non-opioid toll-like receptor 4 (TLR4) antagonist (+)-naltrexone throughout the morphine regimen prevented morphine-induced amplification of SNAP. Exploration of changes induced by early post-trauma morphine revealed that this elevated gene expression of TLR4, TNF, IL-1β, and NLRP3, as well as IL-1β protein at the site of spinal cord injury. These data suggest that a short course of morphine administered early after spinal trauma can exacerbate CNP in the long term. TLR4 initiates this phenomenon and, as such, may be potential therapeutic targets for preventing the deleterious effects of administering opioids after traumatic injury.

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“…83 Briefly, laminectomy was performed at the T12 vertebral level and the dura mater was incised over the dorsal root entry zone. The T13 and L1 dorsal rootlets were carefully isolated and then clamped at the dorsal root entry zone and briskly pulled out (avulsed).…”

Section: Methodsmentioning

confidence: 99%

Systemic Administration of Propentofylline, Ibudilast, and (+)-Naltrexone Each Reverses Mechanical Allodynia in a Novel Rat Model of Central Neuropathic Pain

Ellis

Wieseler

Favret

et al. 2014

The Journal of Pain

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Central neuropathic pain (CNP) is a debilitating consequence of central nervous system (CNS) damage for which current treatments are ineffective. To explore mechanisms underlying CNP, we developed a rat model involving T13/L1 dorsal root avulsion. The resultant dorsal horn damage creates bilateral below-level (L4-6) mechanical allodynia. This allodynia, termed spinal neuropathic avulsion pain (SNAP), occurs in the absence of confounding paralysis. To characterize this model, we undertook a series of studies aimed at defining whether SNAP could be reversed by any of 3 putative glial activation inhibitors, each with distinct mechanisms of action. Indeed, the phosphodiesterase inhibitor propentofylline, the macrophage migration inhibitory factor (MIF) inhibitor ibudilast, and the toll-like receptor 4 (TLR4) antagonist (+)-naltrexone each reversed below-level allodynia bilaterally. Strikingly, none of these impacted SNAP upon first administration but required 1–2 wk of daily administration before pain reversal was obtained. Given reversal of CNP by each of these glial modulatory agents, these results suggest that glia contribute to the maintenance of such pain and enduring release of MIF and endogenous agonists of TLR4 is important for sustaining CNP. The markedly delayed efficacy of all 3 glial modulatory drugs may prove instructive for interpretation of apparent drug failures after shorter dosing regimens.

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Unilateral T13 and L1 Dorsal Root Avulsion: Methods for a Novel Model of Central Neuropathic Pain

Cited by 4 publications

References 20 publications

Segmental Spinal Root Avulsion in the Adult Rat: A Model To Study Avulsion Injury Pain

Segmental Spinal Root Avulsion in the Adult Rat: A Model To Study Avulsion Injury Pain

Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury

Systemic Administration of Propentofylline, Ibudilast, and (+)-Naltrexone Each Reverses Mechanical Allodynia in a Novel Rat Model of Central Neuropathic Pain

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