Allodynia in rats infected with varicella zoster virus—a small animal model for post-herpetic neuralgia

Dalziel, Robert; Bingham, Sharon; Sutton, David; Grant, D.A.D.; Champion, Jean M.; Dennis, Shelley A; Quinn, John P.; Bountra, C.; Mark, M.A

doi:10.1016/j.brainresrev.2004.07.008

Cited by 61 publications

(75 citation statements)

References 68 publications

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“…This may explain the observation that post-herpetic neuralgia is much more common and severe in VZV reactivation than in HSV-1 reactivation. Our findings may provide a mechanism that explains the observation that chronic allodynia developed following VZV infection but not HSV-1 infection in rats (Dalziel et al, 2004). Since IE63 is also expressed during the immediate early phase of productive infection (Debrus et al, 1995), the increase of CGRP release observed here may occur during reactivation.…”

Section: Discussionsupporting

confidence: 51%

Two alphaherpesvirus latency-associated gene products influence calcitonin gene-related peptide levels in rat trigeminal neurons

Hamza

Higgins

Ruyechan

2007

Neurobiology of Disease

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Herpes simplex virus type-1 (HSV-1) initially infects mucoepithelial tissues of the eye and the orofacial region. Subsequently, the virus is retrogradely transported through the axons of the trigeminal sensory neurons. HSV-1 establishes a life-long latent infection in these neurons, during which the transcription of the viral genome is silent, except for the sequences encoding the latency associated transcript (LAT). To determine if HSV-1 latency might affect calcitonin gene-related peptide (CGRP) expression in trigeminal sensory neurons, we transfected primary neuronal cultures of trigeminal ganglia from rat embryos with plasmids expressing LAT. In the presence of Bone Morphogenetic Protein-7 (BMP7), CGRP was expressed in 49% of sensory neurons. However, this percentage was reduced to 19% in neurons transfected with LAT expressing plasmids. We also found that transfection of the IE63 gene of varicella-zoster virus (VZV) reduced the percentage of trigeminal neurons containing CGRP. However, the observed effect of IE63 in contrast to that of LAT, was completely reversed by treatment of cultures with MgCl 2 , which indicates that the effect of IE63 was due to increased release of CGRP from trigeminal neurons. We provide here the first evidence that HSV-1 LAT decreases the level of CGRP in trigeminal neurons. These effects may be important for reducing the neuroinflammatory response, thus protecting host neuronal cells during HSV-1 latency in trigeminal neurons. In contrast, increased release of CGRP in the presence of IE63 protein may contribute to the neuralgias associated with VZV infection.

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Section: Discussionsupporting

confidence: 51%

Two alphaherpesvirus latency-associated gene products influence calcitonin gene-related peptide levels in rat trigeminal neurons

Hamza

Higgins

Ruyechan

2007

Neurobiology of Disease

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“…in viral inoculum concentration. Specifically, the thermal hyperalgesia reported by Garry et al, (2005) was only seen at very high viral concentrations, in excess of those used in our study.Further, we have further demonstrated not only the presence of viral protein (IE62) in sensory neurons following infection with different viral strains, which further supports the initial findings of Dalziel et al, (2004) and Garry et al, (2005), but also the percentage distribution between strains, and a cell size distribution analysis identifying VZV in both small and large cells. It would appear that in general there is a correlation between the amount of viral protein in sensory ganglia and the degree of mechanical hypersensitivity.…”

supporting

confidence: 70%

“…Immunohistochemical analysis of rat dorsal root ganglia (DRG) by Garry et al, (2005) later confirmed the presence of a viral immediate-early gene protein (IE62) in both myelinated Aand unmyelinated C-afferent sensory neurons. However, none of the animal models described to date (Myers et al, 1985;Sadzot-Delvaux et al, 1990;Myers and Connelly, 1992; FleetwoodWalker et al, 1999;Dalziel et al, 2004;Garry et al, 2005) reproduce VZV pathophysiology completely and there is still the need to refine current models to better reflect the clinical scenario.Our study further characterises the rat model of VZV infection described by Fleetwood-Walker et al, (1999) and specifically extends behavioural paradigms beyond stimulus-evoked reflex limb withdrawal paradigms conventionally employed in pain models, to encompass more complex outcome measures of integrated pain behaviour reflecting neuropathic pain comorbidities, in particular anxiety-like behaviour in the open field paradigm. This is of importance as patients with neuropathic pain frequently suffer considerable co-morbidity (e.g.…”

mentioning

confidence: 99%

Further characterization of a rat model of varicella zoster virus–associated pain: Relationship between mechanical hypersensitivity and anxiety-related behavior, and the influence of analgesic drugs

et al. 2007

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Persistent herpes zoster-associated pain is a significant clinical problem and an area of largely unmet therapeutic need. Progress in elucidating the underlying pathophysiology of zoster-associated pain and related co-morbidity behaviour, in addition to appropriately targeted drug development has been hindered by the lack of an appropriate animal model. This study further characterises a recently developed rat model of zoster-associated hypersensitivity and investigates (a) response to different viral strains; (b) relationship between viral inoculum concentration ('dose') and mechanical hypersensitivity ('response'); (c) attenuation of virus-associated mechanical hypersensitivity by clinically useful analgesic drugs; and (d) measurement of pain co-morbidity (anxiety-like behaviour) and pharmacological intervention in the open field paradigm (in parallel with models of traumatic peripheral nerve injury). VZV was propagated on fibroblast cells before subcutaneous injection into the glabrous footpad of the left hind limb of adult male Wistar rats. Control animals received injection of uninfected fibroblast cells. Hind-limb reflex withdrawal thresholds to mechanical, noxious thermal and cooling stimuli were recorded at specified intervals post-infection. Infection with all viral strains was associated with a dose-dependent mechanical hypersensitivity but not a thermal or cool hypersensitivity. Systemic treatment with intraperitoneal (i.p.) morphine (2.5mg/kg), amitriptyline (10mg/kg), gabapentin (30mg/kg), (S)-(+)-ibuprofen (20mg/kg) and the cannnabinoid WIN55,212-2 (2mg/kg) but not the antiviral, acyclovir (50mg/kg), was associated with a reversal of mechanical paw withdrawal thresholds. In the open field paradigm, virus-infected and nerve-injured animals demonstrated an anxiety-like pattern of ambulation (reduced entry into the central area of the open arena) which was positively correlated with mechanical hypersensitivity. This may reflect painrelated comorbidity. Further, anxiety-like behaviour was attenuated by acute i.p. administration of gabapentin (30mg/kg) in nerve-injured, but not virus-infected animals. This model will prove useful Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2008 May 22. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript in elucidating the pathophysiology of zoster-associated pain and provide a tool for pre-clinical screening of analgesic drugs. Keywordszoster-associated pain; postherpetic neuralgia; neuropathy; analgesia; open f...

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“…19,89 However, antiviral therapy does not prevent pain in all patients, 79,89,90 as was also identified in an animal model. [40][41][42][43] The supplementation of antiviral therapy with corticosteroids can be beneficial. 16,91 Combined antiviral therapy with analgesic agents may also be beneficial.…”

Section: Clinical Treatmentsmentioning

confidence: 99%

Postherpetic Neuralgia: From Preclinical Models to the Clinic

et al. 2009

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Summary: Postherpetic neuralgia (PHN), a common complication of herpes zoster, which results from reactivation of varicella zoster virus, is a challenging neuropathic pain syndrome. The incidence and severity of herpes zoster and PHN increases with immune impairment or age and may become a greater burden both in terms of health economics and individual suffering. A clearer understanding of the underlying mechanisms of this disease and translation of preclinical outcomes to the clinic may lead to more efficacious treatment options. Here we give an overview of recent findings from preclinical models and clinical research on PHN.

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Allodynia in rats infected with varicella zoster virus—a small animal model for post-herpetic neuralgia

Cited by 61 publications

References 68 publications

Two alphaherpesvirus latency-associated gene products influence calcitonin gene-related peptide levels in rat trigeminal neurons

Two alphaherpesvirus latency-associated gene products influence calcitonin gene-related peptide levels in rat trigeminal neurons

Further characterization of a rat model of varicella zoster virus–associated pain: Relationship between mechanical hypersensitivity and anxiety-related behavior, and the influence of analgesic drugs

Postherpetic Neuralgia: From Preclinical Models to the Clinic

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