Varicella zoster virus induces neuropathic changes in rat dorsal root ganglia and behavioral reflex sensitisation that is attenuated by gabapentin or sodium channel blocking drugs.
Reactivation of latent varicella zoster virus (VZV) within sensory trigeminal and dorsal root ganglia (DRG) neurons produces shingles (zoster), often accompanied by a chronic neuropathic pain state, post-herpetic neuralgia (PHN). PHN persists despite latency of the virus within human sensory ganglia and is often unresponsive to current analgesic or antiviral agents. To study the basis of varicella zoster-induced pain, we have utilised a recently developed model of chronic VZV infection in rodents. Immunohistochemical analysis of DRG following VZV infection showed the presence of a viral immediate early gene protein (IE62) co-expressed with markers of A- (neurofilament-200; NF-200) and C- (peripherin) afferent sensory neurons. There was increased expression of neuropeptide Y (NPY) in neurons co-expressing NF-200. In addition, there was an increased expression of alpha2delta1 calcium channel, Na(v)1.3 and Na(v)1.8 sodium channels, the neuropeptide galanin and the nerve injury marker, Activating Transcription Factor-3 (ATF-3) as determined by Western blotting in DRG of VZV-infected rats. VZV infection induced increased behavioral reflex responsiveness to both noxious thermal and mechanical stimuli ipsilateral to injection (lasting up to 10 weeks post-infection) that is mediated by spinal NMDA receptors. These changes were reversed by systemic administration of gabapentin or the sodium channel blockers, mexiletine and lamotrigine, but not by the non-steroidal anti-inflammatory agent, diclofenac. This is the first time that the profile of VZV infection-induced phenotypic changes in DRG has been shown in rodents and reveals that this profile appears to be broadly similar (but not identical) to changes in other neuropathic pain models.
Garry
Emer M
EM
Division of Veterinary Biomedical Sciences, Centre for Neuroscience Research, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, UK.
Delaney
Ada
A
Anderson
Heather A
HA
Sirinathsinghji
Eva C
EC
Clapp
Rachel H
RH
Martin
William J
WJ
Kinchington
Paul R
PR
Krah
David L
DL
Abbadie
Catherine
C
Fleetwood-Walker
Susan M
SM
D000588:Amines / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D000077206:Gabapentin; D019004:Galanin / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism / Q000503:physiopathology / Q000821:virology*; D006562:Herpes Zoster / Q000378:metabolism / Q000517:prevention & control / Q000821:virology; D014645:Herpesvirus 3, Human / Q000187:drug effects* / Q000502:physiology; D017874:Immediate-Early Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D000077213:Lamotrigine; D008801:Mexiletine / Q000494:pharmacology* / Q000627:therapeutic use; D009437:Neuralgia / Q000209:etiology* / Q000517:prevention & control; D051474:Neuralgia, Postherpetic / Q000517:prevention & control / Q000821:virology; D009475:Neurons, Afferent / Q000378:metabolism; D009478:Neuropeptide Y / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology* / Q000627:therapeutic use; D014759:Viral Envelope Proteins / Q000378:metabolism; D017735:Virus Latency / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology* / Q000627:therapeutic use
D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; C074221:IE62 protein, Human herpesvirus 3; D017874:Immediate-Early Proteins; D009478:Neuropeptide Y; D016194:Receptors, N-Methyl-D-Aspartate; D015222:Sodium Channels; D015534:Trans-Activators; D014227:Triazines; D014759:Viral Envelope Proteins; D008801:Mexiletine; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D019004:Galanin; D000077213:Lamotrigine