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Oxaliplatin causes peripheral neuropathy as a major dose-limiting side effect, and the control of this neuropathy is difficult. This study was designed to investigate whether prophylactic repetitive administration of 5-HT1A receptor agonists inhibits oxaliplatin-induced mechanical allodynia in mice. Repetitive administration of 5-HT1A receptor agonists (xaliproden and tandospirone) inhibited mechanical allodynia induced by a single intraperitoneal injection of oxaliplatin. These agonists also inhibited oxaliplatin-induced mast cell migration, which is involved in the induction of mechanical allodynia. These results suggest that the prophylactic repetitive administration of 5-HT1A receptor agonists attenuates oxaliplatin-induced mechanical allodynia by inhibiting the cutaneous mast cell migration.

Bortezomib, an inhibitor of proteasome holoenzyme, is used to treat relapsed and refractory multiple myeloma. Peripheral neuropathy is a treatment-limiting adverse effect of bortezomib and is very difficult to control. In this study, we examined the efficacy of gabapentin in inhibiting bortezomib-induced peripheral neuropathy. Single intravenous injections of bortezomib (0.03 – 0.3 mg/kg) dose-dependently induced mechanical allodynia with a peak effect 12 days after injection. Bortezomib (0.3 mg/kg) also caused mechanical hyperalgesia, but neither affected thermal nociception nor induced cold allodynia. Bortezomib increased the response of the saphenous nerve to weak punctate stimulation but not response to cool stimulation of the skin. When administered 12 days after bortezomib injection, oral and intracisternal gabapentin markedly inhibited mechanical allodynia. Intrathecal, but not intraplantar, gabapentin had a tendency to reduce mechanical allodynia. The antiallodynic activity of orally administered gabapentin was suppressed by noradrenaline, but not serotonin, depletion in the spinal cord. Bortezomib did not affect the expression levels of the calcium channel α2δ-1 subunit, a high-affinity binding site of gabapentin, in the plantar skin, spinal cord, medulla oblongata, and pons. These results suggest that gabapentin inhibits bortezomib-induced mechanical allodynia, most likely through the activation of the descending noradrenergic system. Keywords:: bortezomib, gabapentin, allodynia, descending noradrenergic system, noradrenaline

Effects of chlorogenic acid on surfactant-induced itching were studied in mice. Topical application of sodium laurate increased hind-paw scratching, an itch-related response, 2 h after application, which was inhibited by topical post-treatment with chlorogenic acid. Sodium laurate increased the histamine content and 53-kDa l-histidine decarboxylase in the epidermis, which were also inhibited by post-treatment with chlorogenic acid. These results suggest that topical chlorogenic acid is effective in the prevention of itching induced by anionic surfactants. The inhibitory activity of chlorogenic acid may be due to the inhibition of an increase in histamine in the epidermis. Keywords:: chlorogenic acid, sodium laurate–induced itching, histamine in keratinocyte

We investigated whether milnacipran, a serotonin–noradrenaline reuptake inhibitor, exhibits an antipruritic effect through the spinal action in mice. Intrathecal injections of milnacipran (0.1 – 10 μg/site) significantly suppressed serotonin-induced biting, which is an itch-related response. However, such an effect was not observed with fluvoxamine (10 μg/site), which is a selective serotonin reuptake inhibitor. Furthermore, an intraperitoneal injection of milnacipran (10 mg/kg) inhibited serotonin-induced biting. When phentolamine (1.0 μg/site), a non-selective α-adrenoceptor antagonist, was intrathecally injected, it inhibited the above response of milnacipran. These results suggest that milnacipran suppresses itching through the inhibition of noradrenaline reuptake in the spinal cord. Keywords:: milnacipran, itch, α-adrenoceptor in spinal cord

We investigated whether the descending noradrenergic system regulates allergic itch. Mosquito allergy of the hind paw elicited biting, an itch-related response, in sensitized mice. The biting was inhibited by intrathecal clonidine and reversed by yohimbine, an α2-adrenoceptor antagonist. The biting was increased by intrathecal pretreatment with the catecholaminergic neurotoxin 6-hydroxydopamine and the α-adrenoceptor antagonist phentolamine but not the serotonergic neurotoxin 5,7-dihydroxytryptamine. We propose that α2-adrenoceptors are involved in the inhibition of allergic itch in the spinal cord and that the descending noradrenergic system exerts a tonic inhibition on the itch signaling. The serotonergic system may not be involved. Keywords:: allergic itch, clonidine, descending noradrenergic system

Glycine is an inhibitory neurotransmitter in the spinal dorsal horn and its extracellular concentration is regulated by glial glycine transporter (GlyT) 1 and neuronal GlyT2. This study was conducted to elucidate the effects of intrathecal injections of GlyT1 and GlyT2 inhibitors on two distinct types of mechanical allodynia, dynamic and static allodynia, in mice with herpetic or postherpetic pain. The GlyT2 inhibitor ALX1393, but not the GlyT1 inhibitor sarcosine, suppressed dynamic and static allodynia at the herpetic and postherpetic stages. Intrathecal ALX1393 suppressed dynamic allodynia induced by intrathecal strychnine and N-methyl-d-aspartate (NMDA). Intrathecal sarcosine suppressed dynamic allodynia induced by intrathecal strychnine, but not NMDA. Expression level of GlyT1, but not GlyT2, mRNA in the lumbar dorsal horn was decreased at the herpetic and postherpetic stages. Glycine receptor α1-subunit mRNA was decreased in the lumbar dorsal horn at the herpetic, but not postherpetic stage, without alteration in α3-subunit mRNA. The results suggest that GlyT2 is a potential target for treatment of dynamic and static allodynia in patients with herpes zoster and postherpetic neuralgia. The lack of efficacy of GlyT1 inhibitor may be explained by activation of NMDA receptors and the down-regulation of GlyT1 in the lumbar dorsal horn. Keywords:: dynamic allodynia, herpetic pain, postherpetic neuralgia, glycine transporter, glycine receptor

Abstract.: Recently, we showed that a methanol extract of Ganoderma lucidum inhibits scratching, an itch-related response, induced by intradermal injections of some pruritogens in mice. The present study investigated whether G. lucidum extract would inhibit allergic itch. In mice sensitized with an extract of salivary gland of mosquito (ESGM), an intradermal injection of ESGM elicited scratching, which was suppressed by oral administration of G. lucidum extract (100 and 300 mg/kg). The scratching was inhibited by the H1 histamine–receptor antagonist azelastine, but not by the peripherally acting H1-antagonist terfenadine, at the oral dose of 30 mg/kg. In sensitized mice, ESGM increased the activity of cutaneous nerve, which was suppressed by G. lucidum extract (300 mg/kg). Although terfenadine (30 mg/kg) inhibited plasma extravasation induced by ESGM in the sensitized mice, G. lucidum extract (300 mg/kg) was without effect. These results suggest that G. lucidum extract relieves allergic itch through a peripheral action. The results support the idea that mast cells and H1 histamine receptors are not the primary sites of the antipruritic action of G. lucidum extract. Keywords:: Ganoderma lucidum, itch and scratch, mosquito allergy, cutaneous nerve, plasma extravasation

This study investigated the involvement of tryptase and proteinase-activated receptor (PAR) subtypes in spontaneous scratching, an itch-associated behavior, in NC mice. This strain of mice showed chronic atopy-like dermatitis and severe spontaneous scratching, when kept a long time in a conventional environment. The trypsin-like serine proteinase inhibitor nafamostat mesilate (1 – 10 mg/kg) dose-dependently inhibited spontaneous scratching in mice with dermatitis. The activity of tryptase was increased in the lesional skin, which was inhibited by nafamostat at a dose inhibiting spontaneous scratching. Enzyme histochemistry revealed the marked increase of toluidine blue–stained cells, probably mast cells, with tryptase activity in the dermis of the lesional skin. Intravenous injection of anti-PAR2 antibody suppressed spontaneous scratching of mice with dermatitis. Intradermal injection of the PAR2-activating peptide SLI-GRL-NH2, but not PAR1, 3, 4-activating peptides, elicited scratching at doses of 10 – 100 nmol/site in healthy mice. PAR2-immunoreactivity was observed in the epidermal keratinocytes in healthy and dermatitis mice. These results suggest that PAR2 and serine proteinase(s), mainly tryptase, are involved in the itch of chronic dermatitis. Keywords:: atopic dermatitis, itch, scratching, tryptase, proteinase-activated receptor

This study was conducted to make a new mouse model of neuropathic pain due to injury to a branch of the sciatic nerve. One of three branches (sural, tibial, and common peroneal nerves) of the sciatic nerve was tightly ligated, and mechanical and cool stimuli were applied to the medial part (tibial and common peroneal nerve territories) of the plantar skin. The three types of nerve injuries produced behavioral mechanical hypersensitivities, and the extent of the hypersensitivities after sural and tibial nerve ligation was larger than that of common peroneal nerve ligation. Sural nerve ligation did not affect motor function of the affected hind paw, but tibial and common peroneal nerve ligation produced motor dysfunction. These results suggest that the ligation of the sural nerve is the most suitable for behavioral study. Sural nerve ligation induced behavioral hypersensitivities to mechanical and cool stimuli, which were almost completely inhibited by gabapentin (30 mg/kg). Sural nerve ligation increased spontaneous activity and responses of the wide-dynamic range neurons in the lumbar dorsal horn, which were also almost completely inhibited by gabapentin (30 mg/kg). Sural nerve ligation provides a new mouse model of neuropathic pain, which is easy to prepare and sensitive to gabapentin. Keywords:: neuropathic pain, gabapentin, sural nerve-ligation injury, cold allodynia, mechanical allodynia

This study examined in mice whether limaprost, a prostaglandin E1 analog, would relieve allodynia induced by chemotherapeutic agents. Single intraperitoneal injections of paclitaxel, oxaliplatin, and vincristine sulfate induced and gradually increased mechanical allodynia. Repeated administration of limaprost alfadex inhibited the late, but not early, phase of mechanical allodynia induced by paclitaxel and oxaliplatin, but not vincristine. Paclitaxel and oxaliplatin, but not vincristine, gradually decreased peripheral blood flow, which was prevented by limaprost. These results suggest that limaprost is effective against mechanical allodynia induced by paclitaxel and oxaliplatin, which may be due to inhibition of the decrease in peripheral blood flow. Keywords:: limaprost, chemotherapeutic agent–induced mechanical allodynia, peripheral blood flow

We investigated whether endothelin (ET) would be involved in skin cancer pain in mice. Orthotopic inoculation of B16-BL6 melanoma cells into the plantar region of the hind paw produced marked mechanical allodynia in C57BL/6 mice. Intraplantar injections of the ETA- receptor antagonist BQ-123 (0.3 –3 nmol/site), but not the ETB-receptor antagonist BQ-788 (1 and 3 nmol/site), inhibited mechanical allodynia in mice with grown melanoma. In naive mice, an intraplantar injection of tumor extract (1 and 3 mg/site), which was prepared from the grown melanoma in the paw, produced mechanical allodynia, which was inhibited by BQ-123 and BQ-788 at doses of 3 and 10 nmol/site. An intraplantar injection of ET-1 (1 and 10 pmol/site) elicited licking behavior, which was increased in the melanoma-bearing hind paw. BQ-123 (3 and 10 nmol/site) inhibited licking induced by ET-1 (10 pmol/site). The level of mRNA of ETA, but not ETB, receptor, was significantly increased in the dorsal root ganglia on the inoculated side. Cultured B16-BL6 cells contained ET, and the melanoma mass increased the concentration of ET as it grew bigger. These results suggest that ET-1 and ETAreceptor are at least partly involved in the induction of pain induced by melanoma cell inoculation. Keywords:: cancer pain, endothelin, endothelin receptor, allodynia, licking

The common adverse effect of centrally-injected μ-opioid receptor (μ-OR) agonists is pruritus. This study was conducted using mice to examine whether different subtypes of μ-OR would be responsible for pruritus and analgesia. Intracisternal injections of morphine and morphine-6β-glucronide (M6G), but not M3G, produced an antinociceptive effect. Morphine, but neither M6G nor M3G, induced facial scratching, a pruritus-related response. Facial scratching following morphine was not affected by the μ 1-OR antagonist naloxonazine at doses that inhibited the antinociceptive effects. The results suggest that different subtype and/or splice variants of μ-OR are separately involved in pruritus and antinociception of opioids. Keywords:: morphine, morphine-6β-glucronide, itch

Proteinase-activated receptor-2 (PAR2) participates in itch, but the role of the other subtypes of this receptor remain unknown. To investigate this issue, scratching, an itch-related behavior, was observed following intradermal injections of the activating peptides of PAR1–4 in mice. Activating peptides of PAR1, PAR2, and PAR4, but not PAR3, induced scratching. The antihistamine terfenadine suppressed scratching elicited by activating peptides of PAR1 and PAR4, but not PAR2. These results suggest that PAR1, PAR2, and PAR4 are involved in itch and that histamine is a cause of itch related to PAR1 and PAR4, but not PAR2. Keywords:: proteinase-activated receptor subtype, itch, scratch

In the present study, we investigated whether dynamic and static allodynia would be developed in the affected dermatome in murine models of herpetic pain and postherpetic neuralgia and pharmacologically characterized the allodynia. Inoculation with herpes simplex virus type-1 on the femur induced skin lesions in the dermatome including the plantar region of the hind paw from day 5 to day 21 after inoculation. Dynamic allodynia became apparent in the hind paw from day 3 to at least day 42. Static allodynia was not obvious during the stage of herpetic pain and gradually increased after the lesion healing. Mexiletine hydrochloride (30 mg/kg, p.o.) and ketamine hydrochloride (50 mg/kg, i.p.) produced a moderate attenuation of static but not dynamic allodynia. Diclofenac sodium (50 mg/kg, i.p.) did not affect both static and dynamic allodynia. Gabapentin (30 mg/kg, p.o.) markedly inhibited both static and dynamic allodynia. Developmental and pharmacological differences between static and dynamic allodynia suggest that independent mechanisms are responsible for dynamic and static allodynia. This murine model may be useful for the study of the mechanisms of dynamic allodynia of herpetic pain or postherpetic neuralgia and the development of new analgesics effective against the dynamic allodynia. Keywords:: dynamic and static allodynia, herpes simplex virus type-1, herpetic pain, postherpetic neuralgia, dorsal root ganglion

This study investigated endogenous mediators involved in mosquito allergy-associated itching in mice. An intradermal injection of an extract of mosquito salivary gland elicited marked scratching in sensitized mice. The 5-lipoxygenase inhibitor zileuton (100 mg/kg), the 5-lipoxygenase activating peptide inhibitor MK-886 (10 mg/kg), and the glucocorticoid betamethasone 17-valerate (3 mg/kg) inhibited the scratching. The scratching was not affected by the cyclooxygenase inhibitors indomethacin and ketoprofen, the TP prostanoid receptor antagonist SQ-29548, the leukotriene B4 antagonist ONO-4057, the cysteinyl leukotriene antagonist pranlucast, the leukotriene D4 antagonist MK-571, the platelet-activating factor antagonist CV-3988, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester, the H2 histamine-receptor antagonist cimetidine, the H1 histamine-receptor antagonist terfenadine plus cimetidine, and cypoheptadine that blocks the 5-HT1/2 serotonin receptors. Zileuton (100 mg/kg) inhibited the increased activity of the cutaneous nerve branch induced by an intradermal injection of the extract, suggesting the peripheral action. Zileuton and MK-886 (10 and 100 µM) did not affect high K+-induced increase in intracellular Ca2+ concentration in cultured dorsal root ganglion neurons. The results suggest that 5-lipoxygenase metabolite(s) other than leukotriene B4 and cysteinyl leukotrienes are involved in mosquito allergy-associated itching. Keywords:: itch of mosquito allergy, 5-lipoxygense metabolite, zileuton, cutaneous nerve branch, dorsal root ganglion neuron

In the present study, we investigated whether the peripherally acting µ-opioid receptor agonist loperamide would inhibit allodynia in the non-inflamed dermatome of mice with herpetic pain. Subcutaneous (s.c.) injection of loperamide (1 and 3 mg/kg) inhibited allodynia. Local (intraplantar) injection of loperamide (1 and 5 µg/site) also produced an anti-allodynic effect. The peripheral opioid receptor antagonist naloxone methiodide (0.1 mg/kg, s.c.) and the µ-opioid receptor-selective antagonist β-funaltrexamine (40 nmol/site, intraplantar and 20 mg /kg, s.c.) antagonized the anti-allodynic effects of systemic and local loperamide. Local injection of loperamide into the contralateral hind paw was without effect, suggesting that the effect is mediated through local action, not systemic action. Acute and subacute tolerance did not develop to the anti-allodynic effect of loperamide. In addition, there were no cross-tolerance between local opioids (morphine and loperamide) and systemic morphine. These results suggest that stimulation of peripheral µ-opioid receptors suppresses herpetic allodynia without tolerance development. The non-narcotic µ-opioid receptor agonist loperamide may relieve acute herpetic pain in patients with herpes zoster. Keywords:: acute herpetic pain, allodynia, loperamide, peripheral opioid receptor, tolerance

Unsei-in inhibits substance P (SP)-induced scratching of mice after repeated administration. The involvement of cutaneous nitric oxide (NO) in the SP-induced scratching led us to investigate the effects of Unsei-in on the cutaneous NO system in mice. Seven-day oral administration of Unsei-in (300, but not 100, mg/kg daily) significantly inhibited scratching and the increase of cutaneous NO after intradermal SP injection. The NO synthase 1 (NOS1) inhibitor 7-nitroindazole (1 nmol/site) decreased SP-induced scratching and NO production. Repeated administration of Unsei-in (300 mg/kg) reduced the cutaneous NOS1 level. The results suggest that the inhibition of cutaneous NOS1 expression and NO production participates in the antipruritic action of Unsei-in. Keywords:: Unsei-in, nitric oxide synthase 1, itch-associated response

We examined whether azelastine would inhibit itch-associated responses of mice to mosquito allergy. Repeated injections of mosquito salivary gland extract increased scratching and sensory nerve activity. Azelastine inhibited the increased scratching and nerve activity, while terfenadine was without effects. Dexamethasone did not affect the increased scratching. Azelastine suppressed high K+-induced increase in intracellular free Ca2+ in primary cultures of mouse sensory neurons. Direct inhibition by azelastine of sensory neurons may be at least involved in the anti-pruritic effect of azelastine. Histamine, substance P, and leukotriene B4 may not play a key role in the itching of mosquito allergy.

Melanoma inoculation induced marked mechanical allodynia and hyperalgesia in the periphery of the melanoma mass in mice from about day 10 post-inoculation. In the middle of the tumor, there were slight hyperalgesia and response disappearance in the early and late phases, respectively. PGP9.5-like immunoreactivities increased in the epidermis of the periphery of the tumor and disappeared from the dermis of the middle on day 18 post-inoculation, without apparent alterations on day 10. When using this pain model, one should consider the tumor site-dependent responses.

Percutaneous inoculation with herpes simplex virus type-1 brings about herpes zoster-like skin lesions, tactile allodynia, and mechanical hyperalgesia in mice. This study was conducted to determine whether the sympathetic nervous system and α-adrenoceptors would be involved in these pain-related responses and whether the α2-adrenoceptor agonist clonidine would suppress these responses. The adrenergic neuron blocker guanethidine and the non-selective α-adrenoceptor antagonist phentolamine did not affect the pain-related responses, although these agents suppressed the pain-related responses induced by partial ligation of the sciatic nerve. The pain-related responses induced by herpetic inoculation was suppressed by intraperitoneal and intrathecal injections, but not by intraplantar and intracerebroventricular injections, of clonidine. The suppressive effect of an intraperitoneal injection of clonidine (0.1 mg/kg) was antagonized by intrathecal injections of phentolamine and the α2-adrenoceptor antagonist yohimbine, but not the a1-adrenoceptor antagonist prazosin. The results suggest that sympathetic nerves and α-adrenoceptors are not involved in the pain-related responses induced by herpetic infection. Clonidine suppresses the responses probably through the action on α2-adrenoceptors in the dorsal horn.