neuropeptide-y and Herpes-Zoster

Inoculation of rodents with varicella-zoster virus (VZV) results in a latent infection in dorsal root ganglia with expression of at least five of the six VZV transcripts and one of the viral proteins that are reported to be expressed during latency in human ganglia. Rats develop allodynia and hyperalgesia in the limb distal to the site of injection and the resulting exaggerated withdrawal response to stimuli is reduced by treatment with gabapentin and amitryptyline, but not by antiviral therapy. Inoculation of rats with VZV mutants show that most viral genes are dispensable for latency, but that some genes (e.g., ORF4, 29, and ORF63) that are expressed during latency are important for the establishment of latency in rodents, but not for infection of rodent ganglia. The rodent model for VZV latency allows one to study ganglia removed immediately after death, avoiding the possibility of reactivation, and helps to identify VZV genes required for latency.

Topics: Activating Transcription Factor 3; Animals; Animals, Newborn; Disease Models, Animal; Galanin; Ganglia, Spinal; Herpes Zoster; Herpesvirus 3, Human; Humans; Neuropeptide Y; Rats; Sigmodontinae; Virus Latency

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.

Topics: Amines; Animals; Anticonvulsants; Behavior, Animal; Cyclohexanecarboxylic Acids; Disease Models, Animal; Fluorescent Antibody Technique; Gabapentin; Galanin; gamma-Aminobutyric Acid; Ganglia, Spinal; Herpes Zoster; Herpesvirus 3, Human; Immediate-Early Proteins; Immunohistochemistry; Lamotrigine; Mexiletine; Neuralgia; Neuralgia, Postherpetic; Neurons, Afferent; Neuropeptide Y; Rats; Receptors, N-Methyl-D-Aspartate; Reflex; Sodium Channels; Trans-Activators; Triazines; Viral Envelope Proteins; Virus Latency