Hideko Arita

The human histocompatibility leukocyte antigen (HLA) haplotype is associated with the onset of postherpetic neuralgia after herpes zoster.

&NA; In some herpes zoster patients, pain persists for more than 3 months or more after healing of vesicular eruptions; this condition is termed postherpetic neuralgia (PHN). We have recently reported the association of the human histocompatibility leukocyte antigens (HLA) haplotype, HLA‐A*3303‐B*4403‐DRB1*1302 with PHN patients; however, it has not been determined whether the haplotype is also associated with herpes zoster that did not develop subsequent PHN. To distinguish whether the haplotype is associated with herpes zoster or the development of PHN, we examined if herpes zoster patients without subsequently PHN are also associated with the HLA haplotype or not. Herpes zoster patients were followed up for more than 6 months, and HLA alleles and haplotypes were compared among the PHN patients (n=52), the herpes zoster patients who did not develop PHN (n=42) and healthy controls (n=125). The frequencies of the risk haplotype in the PHN patients, in the healthy controls and in the herpes zoster patients without subsequent PHN were 16.3, 5.2 and 4.8%, respectively. While the frequency of the risk haplotype was significantly higher in the PHN patients than in the healthy controls (P=0.0006), no difference was observed between the herpes zoster patients without subsequent PHN and the healthy controls. No significant association was found between the duration of symptoms or the site of herpes zoster and the HLA alleles and the haplotype. These results suggest that the HLA‐A*3303‐B*4403‐DRB1*1302 haplotype plays an important role in the development of PHN after herpes zoster, but not in the onset of herpes zoster.

Association of HLA-A*3303-B*4403-DRB1*1302 haplotype, but not of TNFA promoter and NKp30 polymorphism, with postherpetic neuralgia (PHN) in the Japanese population.

Herpes zoster is a common disease caused by reactivation of the varicella zoster virus (VZV). In a small number of herpes zoster patients, pain persists beyond 4 weeks or more after healing of vesicular eruptions; this condition is termed postherpetic neuralgia (PHN). Positive associations of human histocompatibility leukocyte antigens (HLA) class I antigens, A33 and B44, with PHN in the Japanese population have been reported. Our hypothesis is that susceptibility genes to PHN might exist in the HLA region and the study objective is to further examine possible associations of genes in HLA class I, II and III regions, HLA-A, -B, -DRB1, tumor necrosis factor α (TNFA) promoter, and a natural killer cell activating receptor, NKp30 polymorphisms with PHN. Although TNFA or NKp30 in the class III region had been considered as a candidate locus, we found no associations of TNFA promoter or NKp30 polymorphisms with PHN in this study. We demonstrated that HLA-A*3303, -B*4403 and -DRB1*1302 alleles were significantly associated with PHN (P=0.0007 for A*3303, P=0.001 for B*4403 and P=0.001 for DRB1*1302). The frequency of the HLA-A*3303-B*4403-DRB1*1302 haplotype was also significantly higher in the PHN patients than in the healthy controls (P=0.0039). Our results suggest that this haplotype might be related to the pathogenesis of PHN.

Effects of Topical Application of Clonidine Cream on Pain Behaviors and Spinal Fos Protein Expression in Rat Models of Neuropathic Pain, Postoperative Pain, and Inflammatory Pain

Background:Clonidine can effectively reduce pain and/or hypersensitivity. However, the antihypersensitivity effects of clonidine topically applied in cream (CC) have not been investigated. The authors evaluated effects of topical application of CC on pain behaviors and spinal Fos-like immunoreactivity in rats with hypersensitivity. Methods:Clonidine (30, 100, and 300 &mgr;g/g) was prepared in a cream base. In rat models of neuropathic pain, inflammatory pain, and postoperative pain, the authors evaluated effects of CC (0.1 g), topically applied onto the plantar surface of the injured or uninjured paw, on thermal hyperalgesia and mechanical allodynia to von Frey filaments. The authors also evaluated effects of CC on lumbar spinal Fos-like immunoreactivity. Results:In neuropathic rats, CC applied onto the injured paw reduced thermal hyperalgesia and mechanical allodynia dose dependently, whereas CC applied onto the uninjured paw had no effect. The antihypersensitivity effects of CC were antagonized by intraperitoneal yohimbine (10 mg/kg). Further, CC reduced Fos-like immunoreactivity in neuropathic rats. In contrast, CC in a single dose had no effects on hyperalgesia, allodynia, or Fos-like immunoreactivity in rats with inflammatory or postoperative pain. In rats with postoperative pain, CC repeatedly applied for 6 days reduced thermal hyperalgesia, but not mechanical allodynia, in the postoperative days, whereas it had no effects on hyperalgesia or allodynia in those with inflammatory pain. Conclusions:Topical CC in concentrations examined significantly reduced hypersensitivity and lumbar spinal Fos-like immunoreactivity in rats with neuropathic pain, probably through activation of peripherally located &agr;2 adrenoceptors. However, CC was only partially effective and totally ineffective in rats with postoperative pain and inflammatory pain, respectively.

Encephalopathy and rhabdomyolysis induced by iotrolan during epiduroscopy.

PurposeWe describe a complication of epiduroscopy with encephalopathy and rhabdomyolysis associated with the contrast medium iotrolan.Clinical featuresA 76-yr-old man with failed back surgery syndrome underwent epiduroscopy. Sufficient lysis could not be achieved in the epidural space above the level of L4 due to dense adhesions and scar tissue. After epidural injections of iotrolan and mepivacaine, he developed motor weakness and hypoesthesia in both legs, which lasted for three hours. He also became confused, agitated, disoriented, and developed neck stiffness and tremors involving the head and legs. Computed tomography revealed diffuse contrast enhancement within the intracranial cerebrospinal fluid (CSF) spaces, indicating an intraoperative dural tear. Marked increases in serum creatinine phosphokinase and myoglobin indicated subsequent acute rhabdomyolysis. Crystalloid infusion and semi-recumbent positioning facilitated iotrolan absorption from the CSF, and the patient recovered uneventfully.ConclusionsDural tear during epiduroscopy may allow access of contrast media into the CSF. Neurotoxicity secondary to iotrolan within the CSF was a likely contributing factor to the encephalopathy and subsequent rhabdomyolysis. This is an instructive example of the importance of diagnosing inadvertent dural tear during epiduroscopy under iotrolan, for avoidance of adverse events such as encephalopathy and rhabdomyolysis.RésuméObjectifNous décrivons une complication survenue lors d’une épiduroscopie avec le produit de contraste iotrolan consistant en une encéphalopathie et une rhabdomyolyse.Eléments cliniquesUn homme de 76 ans présentant des séquelles d’un échec d’une chirurgie aux rachis a subi une épiduroscopie. Une lyse suffisante n’a pas pu être obtenue dans l’espace péridural au-dessus de L4 à cause d’adhésions denses et de tissus cicatriciels. Suite à des injections péridurales d’iotrolan et de mépivacaïne, il a développé une parésie ainsi qu’une hypoesthésie au niveau des membres inférieurs qui durèrent trois heures. Il est également devenu confus, agité, désorienté, et a développé une raideur du cou et des tremblements de la tête et des jambes. La tomodensitométrie a révélé un rehaussement diffus du produit de contraste dans les espaces intracrâniens du liquide céphalo-rachidien (LCR), indiquant une déchirure péropératoire de la dure-mère. Des augmentations significatives de la créatinine-phosphokinase sérique et de la myoglobine signalant une rhabdomyolyse aiguë ultérieure ont été observées. Une perfusion de cristalloïde ainsi qu’un positionnement semi-allongé ont facilité l’absorption de l’iotrolan du LCR, et le patient s’est rétabli sans problème.ConclusionsLa déchirure de la dure-mère durant l’épiduroscopie peuvent permettre l’injection de produit de contraste dans le LCR. Une neurotoxicité due à l’iotrolan dans le LCR est un facteur qui a possiblement contribué à l’encéphalopathie et à la rhabdomyolyse subséquente. Ceci est un exemple instructif de l’importance du diagnostic de la déchirure de la dure-mère commises par inadvertence durant l’épiduroscopie sous iotrolan, afin d’éviter des complications telles que l’encéphalopathie et la rhabdomyolyse.

Pentazocine-induced antinociception is mediated mainly by μ-opioid receptors and compromised by κ-opioid receptors in mice.

Pentazocine is a widely used mixed agonist-antagonist opioid. Previous animal studies have demonstrated that pentazocine-induced antinociception displayed a ceiling effect characterized by biphasic dose response with a increasing and then descending analgesia like a bell-shaped curve. This study attempted to clarify the mechanisms underlying such dose-response relationships. ddY and C57BL/6J mice received subcutaneous injection of saline or pentazocine (3, 10, 30, 56, or 100 mg · kg−1), at 120 min after subcutaneous injection of saline, a μ-opioid receptor antagonist clocinnamox mesylate (C-CAM) (5 mg · kg−1), a κ-opioid receptor antagonist nor-binaltorphimine (nor-BNI) (10 mg · kg−1), or the combination of C-CAM and nor-BNI. The antinociceptive effects of pentazocine were evaluated using tail pressure, hot plate, tail flick, and acetic acid writhing tests. Without pretreatment with an opioid receptor antagonist, the antinociceptive effects of pentazocine exhibited biphasic bell-shaped dose-response curves peaking at 30 mg · kg−1. C-CAM completely and partly antagonized the antinociception induced by pentazocine at low (3–30 mg · kg−1) and high (56–100 mg · kg−1) doses, respectively. nor-BNI enhanced the antinociception by pentazocine at high doses and turned the later descending portion of the biphasic dose-response curves into a sigmoid curve. The combination of C-CAM and nor-BNI completely abolished the antinociception by pentazocine at all doses. Our results suggest pentazocine produces antinociception primarily via activation of μ-opioid receptors, but at high doses, this μ-opioid receptor-mediated antinociception is antagonized by concomitant activation of κ-opioid receptors. This provides the first reasonable hypothesis to explain the ceiling effects of pentazocine analgesia characterized by a biphasic dose response.

The comparison of effects of processed Aconiti tuber, U50488H and MK-801 on the antinociceptive tolerance to morphine.

In the previous studies, we demonstrated that an oriental herbal medicine, processed Aconiti tuber (PAT), at subanalgesic doses could inhibit or reverse the antinociceptive tolerance to morphine. In the present study, we compared the effect of PAT, trans-(+/-)-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidin)cyclohexyl)-benzeneacetamide methane sulfonate hydrate (U50488H), a selective kappa opioid receptor (KOR) agonist, and (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine-maleate (MK-801), a N-methyl-D-aspartate (NMDA) receptor antagonist, on the antinociceptive tolerance to morphine in the same experimental condition. Mice received subcutaneous morphine (10 mg/kg), and oral PAT at a subanalgesic dose (0.3 g/kg for mechanical or 1.0 g/kg for thermal test), or intraperitoneal U50488H at a subanalgesic dose (3 mg/kg), or MK-801 at a subanalgesic dose (0.1 mg/kg) once daily for 14 days. The mechanical nociceptive threshold was measured before, and at 60 min by tail pressure testing, and thermal nociceptive latency was measured before, and at 30 min by hot plate testing, after daily morphine injections. PAT and U50488H could not only inhibit the development of morphine tolerance but also reverse the already-developed morphine tolerance, while MK-801 could only inhibit the development of morphine tolerance but not reverse the already-developed morphine tolerance, in both mechanical and thermal nociceptive tests. These data suggested that PAT, an indirect-acting KOR agonist, share the common pharmacological property of KOR agonists on morphine tolerance, and that PAT may be superior to some NMDA receptor antagonists which do not reverse already-developed morphine tolerance.

A rabbit model for evaluation of surgical anesthesia and analgesia: characterization and validation with isoflurane anesthesia and fentanyl analgesia.

PurposeWith a clamp test, quantitative estimation of the level of surgical anesthesia/analgesia is not easy. We have developed a rabbit pain model allowing for quantitative evaluation of the level of surgical anesthesia/analgesia using both electrical and mechanical stimuli as simulated surgical stimuli. We evaluated whether this model allows for accurate tracing of dynamically changing levels of surgical anesthesia/analgesia induced by isoflurane and fentanyl.MethodsEight rabbits tracheotomized and vascularly cannulated under 3% isoflurane anesthesia were placed on a sling that allowed for free movement of the head and extremities. After the isoflurane concentration was reduced stepwise to 1.5% and then to 0%, four graded doses of fentanyl (5, 10, 20, and 40 µg·kg−1) were injected intravenously at intervals of 120 min. At each dose, anesthetic/analgesic end-point variables were determined, including the number of animals behaviorally unresponsive to clamping the forepaw (nonresponders) and the threshold voltage of subcutaneous electrical stimulation (2, 5, and 50 Hz) required to evoke the head lift (HLT: pain detection/arousal threshold: sedative/hypnotic index) and the escape movement (EMT: pain tolerance threshold: analgesic index).ResultsWith increasing doses of isoflurane and fentayl, HLTs and EMTs, especially those at 5 Hz, increased dose-dependently and proportionately to increases in the number of nonresponders to clamping the forepaw, a standard indicator of the anesthetic/analgesic level.ConclusionUsing the HLT and EMT, especially at 5 Hz, combined with a clamp test, this rabbit model allows for repeated, quantitative, and distinctive evaluation of the dynamically changing levels of both sedative/hypnotic and analgesic components of surgical anesthesia/analgesia.

Acupuncture stimulation inhibits somato-renal sympathetic A- and C-reflexes in anesthetized rats

Stimulation of peripheral nerve afferent for example tibial nerve by a strong electrical stimulation (rectanfular wave with 20V amplitude; pulse duration of 0.5 ms, 0.3 pulses/sec) can evoke a discharge of the somato-sympathetic reflex which is recorded on the efferent of renal sympathetic nerve. The component of the somato-sympathetic reflex can be divided into two parts: one is related to the transmission of the myelinated afferent fibers with a short lantency (41+/-2 ms) and is defined A-reflex, the other is related to the transmission of the unmyelinated afferent fibers with a long latency (210+/-13 ms) and is defined C-reflex. In the present study, an acupuncture needle (diameter 0.34 mm) was inserted into the hind limbs of the rat, dorsolaterally at the area of acupoint: huantiao (GB30), at a depth of 4-5 mm and was twisted right and left twice every second during recording the somato-renal sympathetic reflex. It was found that acupuncture on the huantiao acupoint significantly inhibited both A- and C-reflexes. There was no different inhibition of the A- and C-reflexes by acupuncture on the right or left side. However acupuncture on the fore limbs of the rat dorsolaterally at the area of acupoint: quchi (LI11) showed no effect on neither A- nor C-reflexes. These results suggest that acupuncture at the same spinal segment of the acupoint inhibits the somatorenal sympathetic reflex.

Anti-hypersensitivity effects of Shu-jing-huo-xue-tang, a Chinese herbal medicine, in CCI-neuropathic rats

AIM OF THE STUDY Shu-jing-huo-xue-tang (SJHXT) (Japanese name: Sokei-kakketu-to), a traditional Chinese herbal medicine composed of 17 crude drugs, has been prescribed over hundreds of years for treatment of chronic pain syndromes. We evaluated if oral SJHXT could suppress neuropathic pain behaviors in rats with chronic constriction injury (CCI) of the sciatic nerve. MATERIALS AND METHODS (1) Rats received repeated oral SJHXT 0.5 or 1.0 g/kg once daily for 14 days starting 24 h after CCI surgery, while neuropathic manifestations were evaluated until day 20 post-CCI. (2) Other groups of rats received single oral SJHXT 1.0 g/kg on day 14 post-CCI. (3) Additional groups of rats received oral SJHXT 1.0 g/kg on day 14 post-CCI, concomitantly with intraperitoneal yohimbine 1 mg/kg or methysergide 5 mg/kg. Neuropathic manifestations, including mechanical allodynia and thermal hyperalgesia, were evaluated with paw withdrawal responses to increasing mechanical pressure and radiant heat, respectively. RESULTS Mechanical allodynia and thermal hyperalgesia developed by day 14 post-CCI. Repeated oral SJHXT for 14 days produced anti-allodynic and anti-hyperalgesic effects that outlasted the period of drug administration. Single oral SJHXT on day 14 also produced significant anti-allodynic and anti-hyperalgesic effects, which were inhibited by yohimbine, an alpha-2 adrenoceptor antagonist, but not by methysergide, a serotonin receptor antagonist. CONCLUSIONS Oral SJHXT produced anti-hypersensitivity effects by actions on alpha-2 adrenoreceptors in CCI-neuropathic rats, and chronic oral administration of SJHXT could produce the long-lasting anti-hypersensitivity effects.

Analgesic effect of intravenous ATP on postherpetic neuralgia in comparison with responses to intravenous ketamine and lidocaine.

PurposeNo study has been performed on the analgesic effect of adenosine 5′-triphosphate (ATP) on postherpetic neuralgia (PHN). We conducted an open-label trial of ATP in patients with PHN, and compared ATP with ketamine and lidocaine.MethodsTwelve patients with PHN were studied. On separate days, ketamine (0.3 mg·kg−1), lidocaine (2 mg·kg−1), and ATP (100 µg·kg−1·min−1 or less for 120 min) were administrated intravenously. The intensity of spontaneous pain as well as tactile allodynia was assessed using a visual analog scale (VAS). When the VAS score for spontaneous pain was decreased by more than 50%, the patient was classified as a responder.ResultsFive, 6, and 6 patients responded to ketamine, lidocaine, and ATP, respectively. In 6 ATP responders, pain relief developed slowly and lasted for 9 (median) h (range: 3–72 h). All 5 ketamine responders and only 1 of 7 ketamine nonresponders responded to ATP (5/5 vs 1/7, P < 0.05, χ2 test) whereas 2 of 6 responders to lidocaine and 4 of 6 nonresponders to lidocaine responded to ATP (2/6 vs 4/6, P > 0.05). The ketamine responders responded to ATP more often than did the lidocaine responders (5/5 vs 2/6, P < 0.05).ConclusionIntravenous ATP exerted slowly developing and long-lasting analgesic effects in half of patients with PHN. Patients with ketamine-responsive PHN were likely to respond to ATP.