Bidirectional two-sample Mendelian randomization analysis reveals a causal effect of interleukin-18 levels on postherpetic neuralgia risk.

Background: Postherpetic neuralgia (PHN) is a debilitating complication of herpes zoster, characterized by persistent neuropathic pain that significantly impairs patients' quality of life. Identifying factors that determine PHN susceptibility is crucial for its management. Interleukin-18 (IL-18), a pro-inflammatory cytokine implicated in chronic pain, may play a critical role in PHN development. Methods: In this study, we conducted bidirectional two-sample Mendelian randomization (MR) analyses to assess genetic relationships and potential causal associations between IL-18 protein levels increasing and PHN risk, utilizing genome-wide association study (GWAS) datasets on these traits. Two IL-18 datasets obtained from the EMBL's European Bioinformatics Institute database which contained 21,758 individuals with 13,102,515 SNPs and Complete GWAS summary data on IL-18 protein levels which contained 3,394 individuals with 5,270,646 SNPs. The PHN dataset obtained from FinnGen biobank had 195,191 individuals with 16,380,406 SNPs. Results: Our findings from two different datasets of IL-18 protein levels suggest a correlation between genetically predicted elevations in IL-18 protein levels and an increased susceptibility to PHN.(IVW, OR and 95% CI: 2.26, 1.07 to 4.78; p = 0.03 and 2.15, 1.10 to 4.19; p =0.03, respectively), potentially indicating a causal effect of IL-18 protein levels increasing on PHN risk. However, we did not detect any causal effect of genetic liability to PHN risk on IL-18 protein levels. Conclusion: These findings suggest new insights into identifying IL-18 protein levels increasing at risk of developing PHN and may aid in the development of novel prevention and treatment approaches for PHN.

Intradermal miR-16-5p targets Akt3 and reduces RTX-induced postherpetic neuralgia-mimic pain in mice.

The molecular mechanisms of refractory pain in postherpetic neuralgia (PHN) patients are not fully understood. PHN may be related to skin abnormality after herpes zoster induced skin lesions. We previously reported 317 differentially expressed microRNAs (miRNAs) in PHN skin compared with the contralateral normal mirror skin. In this study, 19 differential miRNAs were selected and the expression was validated in other 12 PHN patients. The expression levels of miR-16-5p, miR-20a-5p, miR-505-5p, miR-3664-3p, miR-4714-3p and let-7a-5p are lower in PHN skin, which is the same as those in microarray experiment. To evaluate the effects of cutaneous miRNA on PHN, the expression of candidate miRNAs is further observed in resiniferatoxin (RTX) induced PHN-mimic mice model. In the plantar skin of RTX mice, miR-16-5p and let-7a-5p are downregulated, with the same expression trend of PHN patients. In addition, intraplantar injection of agomir-16-5p reduced mechanical hyperalgesia, and improved thermal hypoalgesia in RTX mice. Furthermore, agomir-16-5p down-regulated the expression levels of Akt3, which is the target gene of agomir-16-5p. These results suggest that intraplantar miR-16-5p may alleviate RTX induced PHN-mimic pain by inhibiting the expression of Akt3 in the skin.

Phenotypes and Genotypes in Postherpetic Neuralgia Drug Therapy: A Narrative Mini-review.

Neuropathic pain is a debilitating symptom reported by patients presenting with postherpetic neuralgia (PHN). Efforts to alleviate this pain have been projected to lie in individualization of pharmacological treatment through pain phenotyping and subsequent investigations into the genetic basis of PHN therapy. Understanding the various mechanisms related to these phenotypes can aid in improvement of available treatment options and discovery of new ones. Knowledge and application of genetic variations in PHN, structural proteins, and genes can aid in ascertaining risk, susceptibility to, severity of, and protection from PHN. This review summarizes the most recent information that has been published on phenotypes and genotypes with possible clinical applications and directions for future research.

Electroacupuncture Inhibits Autophagy of Neuron Cells in Postherpetic Neuralgia by Increasing the Expression of miR-223-3p.

Postherpetic neuralgia (PHN) is a complication of herpes zoster viral infection. Its main manifestations are continuous or intermittent burning-like and electroshock-like pain in the affected nerves. Electroacupuncture (EA) is widely used in clinical treatment and exerts effects in alleviating neuropathic pain. In this study, we investigated the effect and underlying mechanism of EA on PHN. Sprague-Dawley rats were treated with resiniferatoxin (RTX) to establish a PHN model and subjected to EA and/or miR-223-3p overexpression (OV) or interference. Mechanical withdrawal latency was measured as an indication of pain sensitivity. Hematoxylin-eosin staining and transmission electron microscopy were performed to observe neuron cell morphology and autophagic vacuoles, respectively. ELISA was performed to detect reactive oxygen species (ROS) production and the levels of tumor necrosis factor- (TNF-) α, inducible nitric oxide synthase (iNOS), interleukin- (IL-) 6, and IL-10. Changes in autophagy and apoptosis-related miRNAs were detected by immunofluorescence and qRT-PCR, respectively. In RTX-treated rats, OV and EA reduced pain sensitivity, decreased the number of eosinophils, and increased that of nerve cells. ROS generation and the levels of TNF-α and iNOS were significantly reduced, while those of IL-6 and IL-10 were increased. OV and EA induced fewer autophagic vacuoles than those in the model group. The expression of autophagy-related protein microtubule-associated protein 1 light chain 3-II, ATG9, and Rab1 was decreased by OV and EA, whereas that of P62 was increased. qRT-PCR revealed that miR-223-3p expression in the model group decreased but was increased by EA. EA inhibits neuron cell autophagy in PHN by increasing miR-223-3p expression.

Genome-wide association study identifies candidate loci associated with chronic pain and postherpetic neuralgia.

BACKGROUND: Human twin studies and other studies have indicated that chronic pain has heritability that ranges from 30% to 70%. We aimed to identify potential genetic variants that contribute to the susceptibility to chronic pain and efficacy of administered drugs. We conducted genome-wide association studies (GWASs) using whole-genome genotyping arrays with more than 700,000 markers in 191 chronic pain patients and a subgroup of 89 patients with postherpetic neuralgia (PHN) in addition to 282 healthy control subjects in several genetic models, followed by additional gene-based and gene-set analyses of the same phenotypes. We also performed a GWAS for the efficacy of drugs for the treatment of pain. RESULTS: Although none of the single-nucleotide polymorphisms (SNPs) were found to be genome-wide significantly associated with chronic pain (p ≥ 1.858 × 10-7), the GWAS of PHN patients revealed that the rs4773840 SNP within the ABCC4 gene region was significantly associated with PHN in the trend model (nominal p = 1.638 × 10-7). In the additional gene-based analysis, one gene, PRKCQ, was significantly associated with chronic pain in the trend model (adjusted p = 0.03722). In the gene-set analysis, several gene sets were significantly associated with chronic pain and PHN. No SNPs were significantly associated with the efficacy of any of types of drugs in any of the genetic models. CONCLUSIONS: These results suggest that the PRKCQ gene and rs4773840 SNP within the ABCC4 gene region may be related to the susceptibility to chronic pain conditions and PHN, respectively.

LncRNA KCNA2-AS regulates spinal astrocyte activation through STAT3 to affect postherpetic neuralgia.

OBJECTIVES: Postherpetic neuralgia (PHN) is the most common complication of herpes zoster, but the mechanism of PHN is still unclear. Activation of spinal astrocytes is involved in PHN. Our study aims to explore whether lncRNA KCNA2 antisense RNA (KCNA2-AS) regulates spinal astrocytes in PHN through signal transducers and activators of transcription 3 (STAT3). METHODS: Varicella zoster virus (VZV)-infected CV-1 cells were injected into rats to construct a PHN model. Primary spinal cord astrocytes were activated using S-Nitrosoglutathione (GSNO). Glial fibrillary acidic protein (GFAP; marker of astrocyte activation), phosphorylated STAT3 (pSTAT3), and KCNA2-AS were analyzed by immunofluorescence and RNA fluorescence in situ hybridization. RNA pull-down and RNA immunoprecipitation were used to detect binding of KCNA2-AS to pSTAT3. RESULTS: KCNA2-AS was highly expressed in the spinal cord tissue of PHN model rats, and was positively correlated with GFAP expression. GFAP was significantly increased in GSNO-induced cells, but the knockdown of KCNA2-AS reversed this result. Meanwhile, pSTAT3 was significantly increased in GSNO-induced cells, but knockdown of KCNA2-AS reduced pSTAT3 within the nucleus while the total pSTAT3 did not change significantly. pSTAT3 bound to KCNA2-AS and this binding increased with GSNO treatment. Furthermore, knockdown of KCNA2-AS in PHN model rats relieved mechanical allodynia. CONCLUSION: Down-regulation of KCNA2-AS alleviates PHN partly by reducing the translocation of pSTAT3 cytoplasm to the nucleus and then inhibiting the activation of spinal astrocytes.

Bioinformatics Analysis of Genes and Mechanisms in Postherpetic Neuralgia.

Objective: Elderly patients are prone to postherpetic neuralgia (PHN), which may cause anxiety, depression, and sleep disorders and reduce quality of life. As a result, the life quality of patients was seriously reduced. However, the pathogenesis of PHN has not been fully elucidated, and current treatments remain inadequate. Therefore, it is important to explore the molecular mechanism of PHN. Methods: We analyzed the GSE64345 dataset, which includes gene expression from the ipsilateral dorsal root ganglia (DRG) of PHN model rats. Differentially expressed genes (DEGs) were identified and analyzed by Gene Ontology. Protein-protein interaction (PPI) network was constructed. The miRNA associated with neuropathic pain and inflammation was found in miRNet. Hub genes were identified and analyzed in Comparative Toxicogenomics Database (CTD). miRNA-mRNA networks associated with PHN were constructed. Results: A total of 116 genes were up-regulated in the DRG of PHN rats, and 135 genes were down-regulated. Functional analysis revealed that variations were predominantly enriched for genes involved in neuroactive ligand-receptor interactions, the Jak-STAT signaling pathway, and calcium channel activity. Eleven and thirty-one miRNAs associated with neuropathic pain and inflammation, respectively, were found. Eight hub genes (S1PR1, OPRM1, PDYN, CXCL3, S1PR5, TBX5, TNNI3, MYL7, PTGDR2, and FBXW2) associated with PHN were identified. Conclusions: Bioinformatics analysis is a useful tool to explore the mechanism and pathogenesis of PHN. The identified hub genes may participate in the onset and development of PHN and serve as therapeutic targets.

Inflammatory cytokine expression in the skin of patients with postherpetic neuralgia.

OBJECTIVE: To assess the expression of inflammatory cytokines in the affected and normal skin of postherpetic neuralgia (PHN) patients. METHODS: Affected skin and normal skin samples were collected from PHN patients. Inflammatory cell infiltration in the dermis were evaluated by hematoxylin-eosin (HE) staining. A human inflammatory protein array containing 40 cytokines was used to assess expression differences between PHN and control skin. Enzyme linked immunosorbent assay (ELISA) kits were used to confirm cytokine expression in 10 PHN patients. RESULTS: HE staining showed that the epidermis of PHN skin was thicker than that of contralateral normal skin. Compared with normal skin, there was more infiltration of inflammatory cells into the dermis of PHN skin. The cytokine array detected the presence of 21/40 cytokines; however, only interleukin (IL)-1α showed differential expression between PHN skin and normal skin. ELISA results for IL-1α, IL-16, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 were consistent with those of cytokine arrays. CONCLUSIONS: Expression of inflammatory cytokines in PHN skin was not significantly altered compared with normal skin. Chronic refractory pain in PHN is not necessarily associated with increased inflammation in the affected skin.

Identification of Candidate Genes Associated with Postherpetic Neuralgia Susceptibility.

BACKGROUND: Postherpetic neuralgia (PHN) is one of the most common complications of herpes zoster (HZ). Heritable factors have been found to play a role in various clinical pain symptoms. However, the effect of gene variability on the susceptibility of PHN remains poorly understood. OBJECTIVES: The aim of this study was to evaluate whether genetic variation in pain pathway genes was associated with PHN susceptibility in the Chinese population. STUDY DESIGN: Case-control study. SETTING: Department of Anesthesiology and Pain Medicine in a university hospital. METHODS: Seventy patients with PHN and 111 patients with HZ without developing PHN were enrolled. All patients received standardized antiviral agents and analgesics as needed during the acute phase of HZ. Twenty-four candidate genetic polymorphisms in 12 genes (IL1B, SCN9A, KCNK9, TRPV1, P2RX7, HTR1A, HTR2A, ADRB1, ADRB2, BDNF, COMT, and OPRM1) were genotyped in all patients. Multivariable logistic regression analyses were used to identify genetic variations associated with PHN susceptibility while controlling for potential confounders. RESULTS: Our results suggested that only variation in P2RX7 gene was associated with PHN susceptibility. The P2RX7 rs7958311 AG heterozygous genotype carriers had a decreased risk for PHN in the overdominant model (odds ratio [OR], 0.40; 95% confidence interval [CI], 0.21-0.77; P = 0.005), and codominant model (OR, 0.44; 95% CI, 0.20-0.98; P = 0.045). The P2RX7 rs7958311 GG homozygote genotype was associated with an increased risk for PHN under a recessive model (OR, 2.15; 95% CI, 1.01-4.56; P = 0.046). There were no significant associations between the other 23 single-nucleotide polymorphisms and PHN susceptibility. LIMITATIONS: Lack of validation cohort to verify the findings. CONCLUSIONS: In the present study in the Chinese population, we found purinergic receptor P2X7 rs7958311 may contribute to PHN development after HZ. Future larger independent cohorts are warranted to replicate these initial findings. KEY WORDS: Herpes zoster, postherpetic neuralgia, polymorphisms.

Association of rs3783641 single-nucleotide polymorphism in GTP cyclohydrolase 1 gene with post-herpetic neuralgia.

Post-herpetic neuralgia (PHN) is a well-established clinical problem with potential severe personal and socioeconomic implications. GTP cyclohydrolase 1 (GCH1) gene, which encodes the rate-limiting enzyme in tetrahydrobiopterin synthesis, has been strongly implicated to be associated with neuropathic pain in previous animal and human studies. The rs3783641 (T > A) single-nucleotide polymorphism (SNP) in the GCH1 gene is functional. Here we examine the association between rs3783641 and PHN. A total of 292 subjects including 103 PHN patients, 87 herpes zoster (HZ) patients and 102 healthy controls were enrolled in this study. The rs3783641 polymorphisms were detected via the high-resolution melting curve (HRM) method. There were statistical differences between PHN group and the other two groups in genotype distribution (P = 0.029 and 0.017, respectively) and allele frequency (P = 0.032 and 0.005, respectively) of rs3783641. The proportion of subjects with AA genotype in the PHN group was significantly lower compared to HZ group and control group (P = 0.026 and 0.016, respectively). The frequency of A allele was lower in the PHN group than in control group (P = 0.005), and the frequency of T allele in the PHN group was higher than in HZ group and control group (P = 0.001 and 0.003, respectively). The results of this study suggest that the rs3783641 SNP in the GCH1 gene is associated with PHN, and the AA genotype showed a protective effect in PHN.

Safety and Efficacy of a Topical Sodium Channel Inhibitor (TV-45070) in Patients With Postherpetic Neuralgia (PHN): A Randomized, Controlled, Proof-of-Concept, Crossover Study, With a Subgroup Analysis of the Nav1.7 R1150W Genotype.

OBJECTIVE: The objective was to evaluate the safety and efficacy of TV-45070 ointment, as a treatment for postherpetic neuralgia, and to explore the response in patients with the Nav1.7 R1150W gain-of-function polymorphism. MATERIALS AND METHODS: This was a randomized, placebo-controlled, 2-period, 2-treatment crossover trial. Patients with postherpetic neuralgia with moderate or greater pain received TV-45070 and placebo ointments, each applied twice daily for 3 weeks. The primary efficacy measure was the difference in change in mean daily pain score from baseline compared with the last week of placebo and active treatment. Secondary endpoints included responder rate analyses and a further exploratory analysis of response in carriers of the Nav1.7 R1150W polymorphism was conducted. RESULTS: Seventy patients were enrolled and 54 completed the study. TV-45070 was safe and well tolerated. No statistical difference was observed between treatments for the primary endpoint. However, the proportion of patients with ≥50% reduction in mean pain scores at week 3 was greater on TV-45070 than on placebo (26.8% vs. 10.7%, P=0.0039). Similarly, a greater proportion of patients on TV-45070 had a ≥30% reduction in mean pain scores at week 3 (39.3% on TV-45070 vs. 23.2% on placebo, P=0.0784). Of note, 63% of patients with the R1150W polymorphism versus 35% of wild-type carriers had a ≥30% reduction in mean pain score on TV-45070 at week 3 (no inferential analysis performed). CONCLUSIONS: The 50% responder analysis suggests a subpopulation may exist with a more marked analgesic response to TV-45070.The trend toward a larger proportion of responders within Nav1.7 R1150W carriers warrants further investigation.

Association of human leukocyte antigen with postherpetic neuralgia in Koreans.

Postherpetic neuralgia (PHN), the most frequent complication of varicella-zoster virus reactivation, is characterized by pain that persists for more than 3 months, often for years after healing of zoster rash. A few studies revealing the association of human leukocyte antigen (HLA) with PHN have been reported, but only in the Japanese. The aim of this study was to investigate the primary HLA locus associated with PHN susceptibility in Koreans. We compared HLA-A, -B, -C, and DRB1 genotypes of 66 PHN patients with those of 54 herpes zoster (HZ) patients without developing PHN and 235 healthy controls. Frequencies of HLA-B*13, B*44, B*15 (B75), DRB1*10:01, and DRB1*12:02 were increased, and those of HLA-C*01, C*12, and DRB1*01:01 were decreased in PHN patients compared to those in controls (each, p < 0.05). Among these alleles, only the frequency of HLA-B*44 was significantly increased in PHN patients compared to that in HZ patients and the change was due to HLA-B*44:03 (PHN vs controls, p = 0.043; PHN vs HZ, p = 0.012). The results suggest that HLA-B*44:03 or other closely linked gene of the major histocompatibility complex is associated with susceptibility to the development of PHN after HZ, but not with the onset of HZ.

Varicella-zoster virus-derived major histocompatibility complex class I-restricted peptide affinity is a determining factor in the HLA risk profile for the development of postherpetic neuralgia.

UNLABELLED: Postherpetic neuralgia (PHN) is the most common complication of herpes zoster and is typified by a lingering pain that can last months or years after the characteristic herpes zoster rash disappears. It is well known that there are risk factors for the development of PHN, such as its association with certain HLA alleles. In this study, previous HLA genotyping results were collected and subjected to a meta-analysis with increased statistical power. This work shows that the alleles HLA-A*33 and HLA-B*44 are significantly enriched in PHN patients, while HLA-A*02 and HLA-B*40 are significantly depleted. Prediction of the varicella-zoster virus (VZV) peptide affinity for these four HLA variants by using one in-house-developed and two existing state-of-the-art major histocompatibility complex (MHC) class I ligand prediction methods reveals that there is a great difference in their absolute and relative peptide binding repertoires. It was observed that HLA-A*02 displays a high affinity for an ∼7-fold-higher number of VZV peptides than HLA-B*44. Furthermore, after correction for HLA allele-specific limitations, the relative affinity of HLA-A*33 and HLA-B*44 for VZV peptides was found to be significantly lower than those of HLA-A*02 and HLA-B*40. In addition, HLA peptide affinity calculations indicate strong trends for VZV to avoid high-affinity peptides in some of its proteins, independent of the studied HLA allele. IMPORTANCE: Varicella-zoster virus can cause two distinct diseases: chickenpox (varicella) and shingles (herpes zoster). Varicella is a common disease in young children, while herpes zoster is more frequent in older individuals. A common complication of herpes zoster is postherpetic neuralgia, a persistent and debilitating pain that can remain months up to years after the resolution of the rash. In this study, we show that the relative affinity of HLA variants associated with higher postherpetic neuralgia risk for varicella-zoster virus peptides is lower than that of variants with a lower risk. These results provide new insight into the development of postherpetic neuralgia and strongly support the hypothesis that one of its possible underlying causes is a suboptimal anti-VZV immune response due to weak HLA binding peptide affinity.

Orally administered selective TRPV1 antagonist, JTS-653, attenuates chronic pain refractory to non-steroidal anti-inflammatory drugs in rats and mice including post-herpetic pain.

Chronic pain refractory to non-steroidal anti-inflammatory drugs (NSAIDs) is a major problem and drugs for such pain are needed. Many studies suggest that transient receptor potential vanilloid type 1 (TRPV1) is associated with NSAID-refractory chronic pain. Therefore, we investigated the involvement of TRPV1 in NSAID-refractory chronic pain using experimental models for NSAID-refractory chronic pain reflecting severe arthritic and postherpetic pain. The selective TRPV1 antagonist JTS-653 {(3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide} reversed mechanical hyperalgesia on day 7 after injection of complete-Freund-adjuvant into the hindpaw in rats at 0.3 mg/kg, whereas indomethacin showed no effect. JTS-653 reduced chronic pain at 0.3 mg/kg in herpes simplex virus-1-inoculated mice that has been reported as NSAID-refractory pain. JTS-653 partially attenuated mechanical hyperalgesia in the L5 spinal nerve ligation model in rats at 0.3 mg/kg, whereas indomethacin showed no effect. Both JTS-653 and indomethacin reduced formalin-induced pain in the second phase, whereas they showed no effect in the first phase. JTS-653 did not affect the nociception of noxious thermal and mechanical stimuli and motor coordination in normal rats. These findings demonstrate the TRPV1 involvement in NSAID-refractory chronic pain reflecting severe arthritic and postherpetic pain. TRPV1 antagonists would be useful for the treatment of NSAID-refractory chronic pain.

Varicella-zoster viruses associated with post-herpetic neuralgia induce sodium current density increases in the ND7-23 Nav-1.8 neuroblastoma cell line.

Post-herpetic neuralgia (PHN) is the most significant complication of herpes zoster caused by reactivation of latent Varicella-Zoster virus (VZV). We undertook a heterologous infection in vitro study to determine whether PHN-associated VZV isolates induce changes in sodium ion channel currents known to be associated with neuropathic pain. Twenty VZV isolates were studied blind from 11 PHN and 9 non-PHN subjects. Viruses were propagated in the MeWo cell line from which cell-free virus was harvested and applied to the ND7/23-Nav1.8 rat DRG x mouse neuroblastoma hybrid cell line which showed constitutive expression of the exogenous Nav 1.8, and endogenous expression of Nav 1.6 and Nav 1.7 genes all encoding sodium ion channels the dysregulation of which is associated with a range of neuropathic pain syndromes. After 72 hrs all three classes of VZV gene transcripts were detected in the absence of infectious virus. Single cell sodium ion channel recording was performed after 72 hr by voltage-clamping. PHN-associated VZV significantly increased sodium current amplitude in the cell line when compared with non-PHN VZV, wild-type (Dumas) or vaccine VZV strains ((POka, Merck and GSK). These sodium current increases were unaffected by acyclovir pre-treatment but were abolished by exposure to Tetrodotoxin (TTX) which blocks the TTX-sensitive fast Nav 1.6 and Nav 1.7 channels but not the TTX-resistant slow Nav 1.8 channel. PHN-associated VZV sodium current increases were therefore mediated in part by the Nav 1.6 and Nav 1.7 sodium ion channels. An additional observation was a modest increase in message levels of both Nav1.6 and Nav1.7 mRNA but not Nav 1.8 in PHN virally infected cells.

[Implication of genetic polymorphism on neuropathic pain].

Various conditions are categorized to neuropathic pain, many of which are intractable requiring investigation using multiple approaches. Genetic polymorphism is one of such research fields that have provided much insight into conditions including postherpetic neuralgia, CRPS and postoperative pains. The research in genetic polymorphism is also expected to help expedite realization of the genomic personalized medicine in that selection and dosage of medication are determined according to each patient's specific set of requirements. In addition, the genetic polymorphism research effort in the field of drug discovery in areas such as metabolism, transporters and receptors is also expected to contribute to the clinical practice by expanding our knowledge in each of those areas.

HLA alleles are associated with postherpetic neuralgia but not with herpes zoster.

OBJECTIVE: In some herpes zoster (HZ) patients, one symptom is problematic; postherpetic neuralgia (PHN), a persistence of pain such as spontaneous pain and stimulus-evoked pain, allodynia or hyperpathia, for more than 6 months after healing of the vesicular eruptions. In our previous study, we reported the association between HLA alleles, HLA-A*33 and B*44, and PHN patients. In this study, we aim to refine the association of these alleles with PHN or HZ using higher-resolution HLA typing technique with an increased sample size. METHODS: HLA allele frequencies were compared in 70 PHN patients, 80 HZ patients, 52 HZ(-) patients, and 140 Japanese controls using HLA typing kits of SSOP protocols. RESULT AND CONCLUSION: The allele frequencies of HLA-A*3303, B*4403, and DRB1*1302 in PHN(+) patients were significantly higher than those in Japanese controls (P=0.00007, P=0.000002, and P=0.0003, respectively). The frequencies of above alleles in PHN(+) patients were also significantly higher than those in PHN(-) patients (P=0.03, P=0.006 and P=0.03, respectively). However, no association was found in comparison of HZ(+) patients and HZ(-). And the frequency of HLA-B*5101 in HZ(-) patients was significantly higher than those in HZ(+) and PHN(+) patients (P=0.003 and P=0.009, respectively) indicating that HLA-B*5101 functions as a protective allele to HZ.

Does apolipoprotein E determine outcome of infection by varicella zoster virus and by Epstein Barr virus?

Over 90% of the population are infected with varicella zoster virus (VZV) but only some develop shingles - caused when the virus reactivates from latency, and only some shingles patients develop post-herpetic neuralgia (PHN), defined as pain continuing for more than about 4 months. Epstein Barr virus (EBV) similarly infects over 90% of the population; some of those infected during teenage or young adult years develop infectious mononucleosis (IM). The reason for these disparities between numbers infected and numbers affected by illness is unknown, but presumably reflects host factor(s). Our previous results showed that apolipoprotein E (APOE) genotype determines susceptibility to, or outcome of, infection in the case of several diseases of known infectious cause. Therefore, we investigated APOE genotypes of shingles, PHN, and IM patients. Our rationale for the previous studies and for investigating VZV was that these micro-organisms use for cell binding and entry the same sites in the cell surface as does the protein apoE, and that consequently, competition with apoE could affect the pathogen's extent of entry and hence extent of the damage caused. The APOE genotypes of shingles and PHN sufferers, and of IM sufferers were determined using restriction fragment length polymorphism. In females, epsilon4 homozygosity confers a risk of shingles and also of IM, and the APOE-epsilon4 allele is protective against PHN whereas APOE-epsilon3 allele is a risk. Our results showing that a host genetic factor influences the development of shingles and PHN in females have clinical significance: they could lead to identification of those (female) patients at greater risk of PHN, thus enabling these people to be targeted for treatment with the most effective drugs.

Specific down-regulation of spinal mu-opioid receptor and reduced analgesic effects of morphine in mice with postherpetic pain.

The analgesic effects of opioid agonists and the expression of mu- and kappa-opioid receptors were compared between mice with herpetic pain and those with postherpetic pain induced by herpetic virus inoculation. Morphine inhibited herpetic pain more effectively than postherpetic pain. Intrathecal injection reduced the analgesic effects of morphine on postherpetic pain, but intracerebroventricular injection did not. The kappa-opioid receptor agonist nalfurafine suppressed herpetic and postherpetic pain to similar degrees. mu-Opioid receptor-like immunoreactivities in the lumbar dorsal horn were markedly decreased at the postherpetic, but not herpetic, stage of pain. In the dorsal root ganglia, the expression of mu-opioid receptor mRNA was significantly decreased in mice with postherpetic pain, whereas the kappa-opioid receptor mRNA level was not altered. These results suggest that specific down-regulation of the mu-opioid receptor in the primary sensory neurons is responsible for the reduced analgesic action of morphine on postherpetic pain. The kappa-opioid receptor may be a useful target for the analgesic treatment of postherpetic neuralgia.