Transient receptor potentials (TRPs) are non-selective cation channels having a high Ca²⁺ permeability. Since the first finding of TRPV1 that is opened by capsaicin, H⁺ and heat (>43°C) in the peripheral terminal of primary-afferent neuron, various types of TRP such as TRPM8 and TRPA1 have been cloned. Thereafter, the TRPs have been found to be involved in the modulation of nociceptive transmission in the central terminal of the neuron. Recent studies have indicated an involvement of the TRPs in a plasticity of synaptic transmission in the central nervous system.

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【緒言】オキサリプラチンは, 結腸・直腸がんに対して有効な白金系抗がん剤である. しかしながら, 半数近くの患者に急性および蓄積性の末梢神経障害が生じ, 日常生活に及ぼす影響は甚大である. 末梢神経障害への対処は重要であるにもかかわらず, いまだ確立された方法はない. 【症例】60歳代, 女性. 再発大腸がんに対してSOX療法が施行されたが, 治療当初より末梢神経障害が発現した. ピリドキサールリン酸エステル水和物や牛車腎気丸を継続服用したが無効であったため, 患部へ1.35％ l-メントール含有軟膏を1日3回, 1回につきおおむね0.5～1 gを両足裏に塗布するよう, 薬局で服薬指導した. 塗布開始当日より症状のすみやかな消失が認められ, その後SOX療法終了までの1カ月間塗布を継続したが症状の再発はみられなかった. 【結論】1.35％ l-メントール含有軟膏の塗布は, オキサリプラチン誘導末梢神経障害の改善に効果的である可能性が示唆された.

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   Dopamine (DA) is the most abundant catecholamine in the brain. The important contribution of DA as a neurotransmitter in the brain is well understood. Compared with the enormous literature devoted to DA actions in the brain, little is known about the roles of DA in the spinal cord. Dopaminergic innervation of the spinal cord is largely derived from cerebral structures. The periventricular, posterior (A11) region of the hypothalamus is the principle source of descending dopaminergic pathways. To understand the mechanisms of antinociception mediated by the descending dopaminergic pathway, we examined the actions of DA on nociceptive transmission using whole-cell patch-clamp recordings from substantia gelatinosa (SG) neurons in spinal cord slices. Bath application of DA produced an outward current in almost all SG neurons examined. The DA-induced outward current was blocked by the addition of K⁺-channel blockers (Cs⁺ and TEA) or GDP-β-S into pipette solution, and was reduced in the presence of Ba²⁺. The DA-induced outward current was mimicked by a D2-like receptor agonist, quinpirole, but not by a D1-like receptor agonist, SKF 38393. In addition, the DA-induced outward current was suppressed by a D2-like receptor antagonist, sulpiride, but not by a D1-like receptor antagonist, SCH 23390. These results indicate that DA acts on postsynaptic SG neurons to induce an outward current by G-proteinmediated activation of K⁺ channels through D2-like receptors. This may be a possible mechanism for antinociception by the descending dopaminergic pathway.

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  We report a patient with Ramsay Hunt syndrome in whom the infusion of adenosine triphosphate (ATP) significantly alleviated neuropathic pain developing as a result of herpes zoster in the trigeminal nerve region.

  The patient was a 74-year-old man who complained of severe pain in the third branch region of the left trigeminal nerve and auricle at the time of his first visit and who exhibited edematous erythema and blisters. Since peripheral facial nerve paralysis appeared 6 days after the initial diagnosis, the administration of a stellate ganglion block (SGB), near-infrared therapy, prednisolone (30 mg/day, gradually decreasing), and mecobalamin (1.5 mg/day) was initiated. Two weeks later, neuropathic pain appeared, so pregabalin (50 mg/day, gradually increasing to 450 mg/day) and amitriptyline (10 mg/day, gradually increasing to 60 mg/day) were additionally administered. After repeated SGB and near-infrared therapy, the facial nerve paralysis nearly disappeared, but the improvement in the neuropathic pain was insufficient.

  Therefore, the intravenous administration of magnesium sulfate hydrate and lidocaine hydrochloride was performed. Since the pain relief was temporary, ATP infusion (100 μg/kg/min) was subsequently performed. The ATP infusion resulted in continuous pain relief ; thereafter, a total of 4 ATP infusions were performed. The pain gradually decreased and ultimately disappeared completely.

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   The incidence of chronic pain among the adult Japanese population has been reported to be around 23%. In the majority of cases, the site of chronic pain is located in the musculoskeletal system, such as the lumbar spine, neck and shoulder joint. Based on the pain mechanism, musculoskeletal chronic pain is classified as chronic nociceptive pain, neuropathic pain or mixed pain. Psycho–social factors often affect clinical symptoms in chronic pain cases.
   The first choice of medication for chronic nociceptive pain, resulting from conditions such as inflammation or degeneration of joints or spine, is nonsteroidal anti–inflammatory drugs (NSAIDs). Cox 2 selective inhibitors should be used in cases of long–term use to avoid gastrointestinal problems. Although opioids may be applied in cases in which NSAIDs have no effect, attention should be paid to potential side effects such as nausea and consti-pation, abuse and addiction. Physical therapy including muscle stretching and strengthening is a very important therapeutic modality for chronic noci-ceptive pain. Surgical treatment, such as arthroplasty and spinal fusion, may also be applied in cases in which conservative treatments fail.
   As NSAIDs are not effective for neuropathic pain caused by disorders and diseases of nervous system, pregabalin (Ca²⁺ channel blocker), anti–depressant s and opioids may be applied. Surgery intervention, including laminectomy, discectomy or neurolysis for the purpose of nerve decompres-sion, may be applied in cases in which conservative treatment fail or nerve palsy is observed. For difficult chronic pain cases with psycho–social factors, a multidisciplinary approach including cognitive behavioral therapy should be considered.

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   The last decade has seen the development of a particular interest in the role of purines in nociception. The ability of adenosine 5'-triphosphate (ATP) and adenosine to alter nociceptive transmission at peripheral and central sites has been recognized. The recent discovery of P2X receptors (ion channels gated by ATP) has led to the exploration of the sources of ATP involved in initiating different types of nociception. In addition, adenosine receptors in the spinal cord have generated great interest in the development of its agonists as potential analgesic drugs. Although each role of P2X and adenosine receptors in nociceptive transmission has been examined in detail, the interaction of their receptors has never been studied. In this study, we demonstrated that extracellular ATP induces a biphasic effect such as facilitation followed by inhibition of glutamatergic excitatory synaptic transmission in dorsal horn neurons of spinal cord slice preparations by use of patch-clamp recordings. The application of ATP made an initial facilitation of glutamate release via presynaptic P2X receptors, which lasted for only a short period. ATP was rapidly metabolized to adenosine which produced an inhibition of glutamate release onto dorsal horn neurons by activating adenosine receptors for a relatively longer period. Our results indicate that extracellular ATP exerts multiple influences on nociceptive transmission in the spinal cord.

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   Intrathecal administration of adenosine analogues is well-known to result in an antinociception in the tail-flick test. Cellular mechanisms for this action of adenosine have not been fully examined yet, particularly in pharmacological properties, although adenosine receptors are classified into some subtypes including A₁ and A_2a receptors. We examined pharmacologically the action of adenosine on glutamatergic excitatory transmission to substantia gelatinosa (SG) neurons of an adult rat spinal cord slice with an attached dorsal root. Superfusing adenosine (100 µM) produced in SG neurons an outward current having a peak amplitude of 15 ± 5 pA (n=6). In 65% of the neurons examined (n=72), adenosine (100 µM) inhibited the frequency of miniature excitatory postsynaptic current (EPSC) in a reversible manner. When examined quantitatively in extent in some cells (n=25), the inhibition was 40 ± 3% (n=25); this was not accompanied by a change in miniature EPSC amplitude. The inhibitory action on miniature EPSC frequency was dose-dependent in a range of 10–500 µM with an EC₅₀ value of 277 µM. The inhibitory action of adenosine was mimicked by a selective A₁ adenosine receptor agonist, N⁶-cyclopentyladenosine (CPA, 1 µM; depression: 54 ± 9%, n=4); this action of adenosine (100 µM) was not observed in the presence of a specific A₁ adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (1 µM). When examined for monosynaptic EPSCs evoked by electrical stimulation of the dorsal root, adenosine (100 µM) inhibited in amplitude Aδ-fiber EPSCs by 40 ± 5% in 9 of 17 neurons examined and C-fiber EPSCs by 34 ± 9% in 5 of 10 neurons examined. A similar inhibitory action was observed by CPA (1 µM). It is concluded that adenosine inhibits excitatory transmission to SG neurons from glutamatergic interneurons and primary-afferent neurons through the activation of presynaptic A₁ adenosine receptors; this could serve to negatively modulate pain transmission to SG neurons from the periphery.

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   Although intrathecal administration of adenosine analogues is known to result in antinociception, cellular mechanisms for this action have not been fully addressed yet. We examined a detail of the actions of adenosine on holding currents, excitatory (glutamatergic) and inhibitory (GABAergic and glycinergic) transmission in substantia gelatinosa (SG) neurons of an adult rat spinal cord slice, and compared their actions in efficacy with each other. Superfusing adenosine (1 mM) induced a current (peak amplitude: 17.6 ± 1.8 pA at -70 mV, n=30) which reversed at a potential being close to the equilibrium potential for K⁺. K⁺-channel inhibitors, Ba²⁺ (100 µM) and 4-aminopyridine (5 mM), reduced the peak amplitude of this current by 65 ± 8% (n=3) and 46 ± 3% (n=3), respectively. An A₁ adenosine-receptor agonist, N⁶-cyclopentyladenosine (CPA, 1 µM), produced a similar outward current having a peak amplitude of 17.6 ± 2.9 pA (n=3) at -70 mV. Adenosine (100 µM) and CPA (1 µM) reduced the peak amplitude of dorsal root-evoked monosynaptic Aδ -fiber EPSCs by 39 ± 5% (n=15) and 50 ± 4% (n=3), respectively. Focally-evoked GABAergic and glycinergic IPSCs in the presence of a non-NMDA receptor antagonist (CNQX) were also reduced in peak amplitude by adenosine [100 µM; by 39 ± 6% (n=6) and 50 ± 7% (n=4), respectively] or CPA [1 µM; by 55 ± 6% (n=3) and 51 ± 17% (n=3), respectively]. All of the adenosine actions were inhibited by an A₁ antagonist, 8-cyclopentyl 1,3-dipropylxanthine (1 µM). With respect to efficacies of adenosine, EC₅₀ values for adenosine in inducing outward currents (hyperpolarizations) and reducing monosynaptic Aδ -fiber EPSC, GABAergic and glycinergic IPSC amplitudes were 130, 130, 24 and 21 µM, respectively. It is concluded in SG neurons that adenosine at low doses depresses inhibitory transmission while adenosine at high doses induces hyperpolarization and inhibits excitatory transmission, all of which are due to the activation of A₁ receptors. Considering that the SG plays a pivotal role in modulating nociceptive transmission from the periphery, it is suggested that adenosine at low and high concentrations may elicit nociception and antinociception, respectively.

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   Marijuana (Cannabis sativa) has a large variety of therapeutic effects including analgesia, all of which are thought to be due to an action of its primary active constituent, ∆⁹-tetrahydrocannabinol, acting on cannabinoid receptors. Endocannabinoids such as N-arachidonoylethanolamide (anandamide) are also known to exert antinociceptive activity in various animal models of acute pain. A subtype of cannabinoid receptors, CB1, is predominantly expressed in the CNS including the spinal superficial dorsal horn. Although a number of studies have examined an action of cannabinoids on synaptic transmission in the CNS, this is not understood fully in the spinal dorsal horn. In order to know a role of cannabinoids in regulating pain transmission, we studied the effects of anandamide and a synthetic cannabinoid-receptor agonist, WIN-55212-2, on excitatory and inhibitory transmission in substantia gelatinosa (SG) neurons of adult rat spinal cord slices by using the blind whole-cell patch-clamp technique. In many of the cells examined, anandamide (10 µM) attenuated the amplitude of either monosynaptic glutamatergic EPSCs through Aδ and C primary-afferent fibers, γ-aminobutyric acid (GABA) or glycine-mediated focally-evoked IPSCs. Spontaneous GABAergic and glycinergic IPSCs were inhibited in frequency but not amplitude by anandamide, while spontaneous EPSCs were unaffected in amplitude and frequency. These actions were mimicked by WIN-55212-2 (5 µM). It is concluded in SG neurons that can nabinoids inhibit the release of L-glutamate from primary-afferent central terminals and also the release of GABA and glycine from interneuron terminals, all of which are possibly due to the activation of the CB1 receptor; these actions would contribute to a modulation of nociceptive transmission to the spinal dorsal horn from the periphery.

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Transient receptor potential (TRP) type-V1 (TRPV1) and TRP type-M8 (TRPM8), expressed in the peripheral terminals of primary-afferent neurons, receive sensory stimuli given to the periphery, while those in the central terminals of the neurons play a role in regulating nociceptive transmission to the CNS. Agonists for the TRPV1, at high concentrations, have an ability to inhibit action potential conduction in nerve fibers. We have previously reported that TRPV1 agonists reduce the peak amplitude of compound action potential (CAP) in the frog sciatic nerve. In order to know whether TRPM8 agonists have a similar action, we examined their actions on CAPs recorded from the frog sciatic nerve by using the air-gap method. A TRPM8 agonist (-) menthol concentration-dependently reduced CAP peak amplitude (IC₅₀ = 1.1 mM). A similar inhibition was seen by (+) menthol, while the (-) menthol-induced CAP inhibition was resistant to a non-selective TRP antagonist ruthenium red and a TRPM8 agonist icilin at 0.02 mM, a concentration being three-fold larger than EC₅₀ value for its activation, did not affect CAPs. When various chemicals, which have p-menthane base and are similar in structure to menthol, were tested, thymol, carvacrol, (-) menthone, (+) menthone, (+) pulegone, menthyl lactate and 1,8-cineole reduced CAP peak amplitude; their IC₅₀ values were 0.42, 0.35, 1.6, 3.2, 1.4, 0.42 and 6.6 mM, respectively. On the other hand, other compounds, p-menthane, (+) limonene, menthylchloride and menthyl acetate at high concentrations such as 7- 10 mM hardly affected CAPs. In conclusion, like TRPV1 agonists, menthol-related compounds reduced CAP peak amplitude without TRPM8 activation. It is suggested that a hydroxyl group bound to p-menthane may play a role in determining the extent of nerve conduction inhibition. This result may serve as information to develop local anesthetics which are similar in chemical structure to menthol.

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　Eugenol (4-allyl-2-methoxyphenol), which is contained in several plants including clove and bay leaves, has been widely used as an analgesic and anti-inflammatory drug in the dental clinic. Furthermore, eugenol has a general anesthetic effect, and produces sedation and the reduction of convulsion threshold. These benefits have been partly attributed to the effects of eugenol on neural tissues. Eugenol depresses the conduction of action potential in nerve fibers and thus serves as a local anesthetic. Voltage-gated Na⁺, Ca²⁺ and K⁺ channels are inhibited by eugenol in rat trigeminal ganglion neurons or dorsal root ganglion (DRG) neurons. As expected from the fact that eugenol and capsaicin share the vanilloid moiety in chemical structure, eugenol activates transient receptor potential (TRP) V1 channels, nonselective cation channels, in rat DRG neurons. Although eugenol is suggested to affect synaptic transmission in the central nervous system, to our knowledge, this has not yet been fully examined. The present study investigated how eugenol affects glutamater-gic spontaneous excitatory transmission in substantia gelatinosa (SG; lamina II of Rexed) neurons of adult rat spinal cord slices by use of the blind whole-cell patch-clamp technique. Bath-applied eugenol reversibly enhanced spontaneous excitatory transmission in SG neurons in a concentration-dependent manner in a range of 1 - 5 mM. This action was due to a large increase in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) with a small increase in the amplitude. Eugenol also produced an outward current at −70 mV. These actions of eugenol were seen by its repeated application and resistant to a voltage-gated Na⁺-channel blocker tetrodotoxin (0.5 µM). The effect of eugenol (5 mM) on sEPSC frequency was unaffected by a TRPV1 channel antagonist capsazepine (10 µM) while inhibited by a non-selective TRP channel antagonist ruthenium red (300 µM). On the other hand, the eugenol-induced outward current was not affected by both of the antagonists. It is concluded that eugenol activates TRP channels other than TRPV1 channels in the SG, leading to an increase in the spontaneous release of L-glutamate to SG neurons and that eugenol also produces a membrane hyperpolarization which is not mediated by TRP channels. The former action could be involved in producing nociception.

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アロマテラピーは気分に変化を及ぼしたり，身体に生理的な変化をおこさせたりする．このような香り物質の効果は，その匂いが嗅覚を介して神経系に情動的に働きかけるいわゆる心理的作用，あるいは香り物質に含まれる化学物質による薬理作用による．ここでは，精油の作用について紹介すると共にアロマテラピーのリハビリテーション分野への利用可能性について述べる．

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There is much evidence showing that a group of neuropeptides produced in the hypo­thalamus, oxytocin and orexins, inhibit nociceptive transmission in the rat spinal dorsal horn. In order to reveal cellular mechanisms underlying this antinociception, we examined how oxytocin, orexins A and B affect spontaneous synaptic transmission in rat spinal lamina II (substantia gelatinosa; SG) neurons, which play a pivotal role in regulating nociceptive transmission. The experiments were performed by applying the blind whole–cell patch–clamp technique to SG neurons in adult rat spinal cord slices. Bath–applied oxytocin unaffected glutamatergic spontaneous excitatory transmission while producing an inward current at −70 mV (membrane depolarization) and enhancing both GABAergic and glycinergic spontaneous inhibitory transmissions in >70% of the neurons tested. The depolarization, and increased GABAergic and glycinergic spontaneous inhibitory postsynaptic current (sIPSC) frequencies were concentration–dependent with half–maximal effective concentration (EC₅₀) values of 0.022, 0.024 and 0.038 µM, respectively. On the other hand, orexins A and B produced an inward current at −70 mV and/or increased the frequency of spontaneous excitatory postsynaptic current (sEPSC) without changing its amplitude in some 70% of the neurons examined. EC₅₀ values for orexin A in their effects were 0.0045 and 0.030 µM, respectively; those for orexin B were 0.020 and 0.039 µM, respectively. EC₅₀ value for orexin B in producing inward current was similar to that of oxytocin while being four–fold larger than that of orexin A; EC₅₀ value for orexin B in increasing sEPSC frequency was comparable to orexin A’s one and also to oxytocin’s ones for sIPSC frequency increase. Like oxytocin, orexin A enhanced both GABAergic and glycinergic transmissions in >50% of the neurons tested, whereas orexin B facilitated glycinergic but not GABAergic transmission in the majority (about 70%) of neurons tested. Inhibitory transmission enhancements produced by oxytocin, orexins A and B dis­appeared in the presence of the voltage–gated Na⁺–channel blocker tetrodotoxin. Oxytocin activities were mimicked by an oxytocin–receptor agonist TGOT and were inhibited by an oxytocin–receptor antagonist dVOT, indicating an activation of oxytocin receptors. Orexin A activities were inhibited by an orexin–1 receptor antagonist (SB334867) but not an orexin–2 receptor antagonist (JNJ10397049) while orexin B activities were inhibited by JNJ10397049 but not SB334867, indicating that orexins A and B activities are mediated by orexin–1 and –2 receptors, respectively. It is concluded that oxytocin, orexins A and B increase neuronal activity through membrane depolari­zation and/or increased _L–glutamate release from nerve terminals, by activating their specific receptors, which in turn results in GABAergic and/or glycinergic spontaneous inhibitory transmission enhancements, a possible mechanism for antinociception.

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Many of analgesics and analgesic adjuvants act on nerve conduction and synaptic transmission in the nervous system to inhibit nociceptive transmission. It has not been fully examined how nerve conduction inhibition leading to antinociception differs in extent among various analgesics and analgesic adjuvants. We examined quantitatively their actions on fast–conducting compound action potentials (CAPs) recorded from the frog sciatic nerve. Drugs tested were local anesthetics, opioids, adrenoceptor agonists, antiepileptics, antidepressants and non–steroidal anti–inflam­matory drugs (NSAIDs). As a result, we found that many of their drugs reduce the peak amplitude of the CAPs in a manner dependent on their chemical structures. Consistent with voltage–gated Na⁺–channel inhibition produced by local anesthetics, CAP peak amplitudes were reduced by procaine, cocaine, tetracaine, prilocaine, lidocaine, ropivacaine, levobupivacaine and pramoxine with the half–maximal inhibitory concentration (IC50) values of 2.2, 0.80, 0.013, 1.8, 0.74, 0.34, 0.23 and 0.21 mM, respectively. A weak opioid tramadol reduced CAP peak amplitude­s (IC₅₀ = 2.3 mM) more effectively than its metabolite mono–O–demethyl–tramadol; this distinction was attributed to such a difference in chemical structure that tramadol and mono–O–demethyl–tramadol have –OCH₃ and –OH bound to a benzene ring, respectively. Moreover, a sequence of CAP peak amplitude reductions produced by various opioids was ethylmorphine (IC₅₀ = 4.6 mM) > codeine > morphine, i.e., this reduction enhanced in extent with an increase in the number of –CH₂. α₂–Adrenoceptor agonist dexmedetomidine reduced CAP peak amplitudes with an IC₅₀ value of 0.40 mM. Other α₂ adrenoceptor agonists, oxymethazoline (IC₅₀ = 1.5 mM) and clonidine, also inhibited CAPs with potencies less than dexmedetomidine while adrenaline, noradrenaline, an α₁ adrenoceptor agonist phenylephrine and a β–adrenoceptor agonist isoproterenol had no effect on CAPs. Antiepileptics, lamotrigine and carbamazepine, reduced CAP peak amplitudes with the IC₅₀ values of 0.44 and 0.50 mM, respectively. CAP peak amplitudes were reduced by a small extent by oxcarbazepine and phenytoin. On the other hand, gabapentin, topiramate and sodium valproate had no effect on CAPs. With respect to antidepressants, amitriptyline, duloxetine, maprotiline, fluoxetine, desipramine and trazodone reduced CAP peak amplitudes with the IC₅₀ values of 0.26, 0.23, 0.95, 1.5, 1.6 and ca. 1.0 mM, respectively. Acetic acid–based NSAIDs (diclofenac and aceclofenac) reduced CAP peak amplitudes with the IC₅₀ values of 0.94 and 0.47 mM, respectively. Other acetic acid–based NSAIDs (indomethacin, etodolac and acemetacin) also inhibited CAPs; sulindac and felbinac had no effect on CAP amplitudes. A similar CAP inhibition was produced by fenamic acid–based NSAIDs [tolfenamic acid, meclofenamic acid and flufenamic acid (IC₅₀ values: 0.29, 0.19 and 0.22 mM, respectively)]. On the other hand, salicylic acid–based (aspirin), propionic acid–based (ketoprofen, ibuprofen, naproxen, loxoprofen and flurbiprofen) and enolic acid–based (meloxicam and piroxicam) NSAIDs had no effect on CAPs. In conclusion, CAP inhibitions produced by local anesthetics were partly comparable in extent to those of α₂ adrenoceptor agonists, antiepileptics, antidepressants and NSAIDs; opioids inhibited CAPs less potently than their drugs. It is suggested that analgesics and analgesic adjuvants inhibit nerve conduction in a manner dependent on their chemical structures.

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   Aroma–oil compounds derived from plants have a variety of clinical effects including local anesthesia. We have previously reported that various aroma–oil compounds reduce the peak amplitudes of fast–conducting and Na⁺–channel blocker tetrodotoxin–sensitive compound action potentials (CAPs) recorded from the frog sciatic nerve in a manner dependent on their chemical structures. The present study further examined this structure–activity relationship by applying the air–gap method to the frog sciatic nerve. Cyclic alcohols ((+)–borneol, (–)–borneol, α–terpineol), chain alcohols ((–)–linalool, citronellol, geraniol) and esters (bornyl acetate, geranyl acetate) reduced CAP peak amplitudes with the half–maximal inhibitory concentration (IC₅₀) values of 1.5 mM, 2.3 mM, 2.7 mM, 2.0 mM, 0.35 mM, 0.53 mM, 0.44 mM and 0.51 mM, respectively. This IC₅₀ value for (–)–linalool was similar to that for (±)–linalool (1.7 mM), a value as reported previously. On the other hand, hydrocarbon (p–cymene) at a high concentration such as 2 mM reduced CAP amplitude by only 20%. The efficacy sequence of the aroma–oil compounds was esters ≧ alcohols ＞ hydrocarbons, and was thus consistent with one reported previously, i.e., phenols ≧ aldehydes ≧ esters ＞ alcohols ＞ ketones ＞ oxides ≫ hydrocarbons. There was a variation in IC₅₀ value among the alcohols used; chain alcohols were more effective in inhibiting CAPs than cyclic ones. Similar IC₅₀ values of (–)–linalool and (±)–linalool and also of (+)–borneol and (–)–borneol indicate no difference in efficacy between the steroisomers in inhibiting CAPs. There was no correlation between IC₅₀ value for CAP inhibition by aroma–oil compound and its octanol–water partition coefficient value. The present study confirmed that aroma–oil compounds inhibit nerve conduction in a manner specific to their chemical structures.

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   Although the application of aroma–oil compounds contained in plants such as lavender to the skin produces a local anesthetic effect, cellular mechanisms for this effect have not been fully examined yet. Since some of aroma oil–derived chemicals modulate transient receptor potential (TRP) channels expressed in primary–afferent neurons, this modulation may be involved in the local anesthetic effect. We have previously reported that plant–derived chemicals (capsaicin, menthol and allyl isothiocyanate, which activate TRPV1, TRPM8 and TRPA1 channels, respectively) at high concentrations inhibit fast–conducting and Na⁺–channel blocker tetrodotoxin–sensitive compound action potentials (CAPs) recorded from the frog sciatic nerve without TRP activation. The CAPs were also inhibited by opioids and adrenoceptor agonists without the activation of receptors for the agonists. The inhibitory actions were specific to their chemical structures. The present study examined how various aroma–oil compounds affect frog sciatic nerve CAPs by using the air–gap method. Lavender–oil compounds, linalyl acetate and linalool, reduced CAP peak amplitudes with the half–maximal inhibitory concentration (IC₅₀) values of 0.49 mM and 1.65 mM, respectively. When compared with local anesthetics’ actions reported previously in the frog sciatic nerve, the linalyl acetate activity was similar to those of lidocaine, ropivacaine and cocaine (0.74, 0.34 and 0.80 mM, respectively), while the linalool one was comparable to that (2.2 mM) of procaine. Citral, which activated TRPV1, TRPM8, TRPA1 and TRPV3 channels, attenuated CAP peak amplitudes with the IC₅₀ value of 0.48 mM; this action was resistant to a non–selective TRP antagonist ruthenium red (0.3 mM). Camphor, a TRPV1 and TRPV3 agonist, also reduced CAP peak amplitudes (by 30％ at 5 mM) in a manner insensitive to ruthenium red. With respect to other aroma–oil compounds, citronellal and rose oxide reduced CAP peak amplitudes with the IC50 values of 0.50 mM and 2.0 mM, respectively, while myrcene at a high concentration such as 5 mM hardly reduced CAP peak amplitudes. Taking into consideration previously–reported frog sciatic nerve data, an efficacy sequence of aroma–oil compounds for the CAP inhibi­tions was phenols (carbacrol: 0.35 mM; thymol: 0.42 mM; eugenol: 0.81 mM) ≧ aldehydes (citral and citronellal) ≧ esters (linaryl acetate) ＞ alcohols (linalool; menthol: 0.93 – 1.1 mM) ＞ ketones (pulegone: 1.4 mM; carbone: 1.4 – 1.6 mM; menthone: 1.5 – 2.3 mM) ＞ oxides (rose oxide; cineole: 6.6 – 7.5 mM) ≫ hydrocarbons (myrcene; limonene: 8％ inhibition at 10 mM), except for a ketone camphor that was less effective than oxides. It is suggested that aroma–oil compounds inhibit nerve conduction in a manner specific to their chemical structures; some of the compounds have efficacies comparable to those of local anesthetics. This result would serve to know aroma–oil compounds which may be useful as local anesthetics.

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The effect of fertilizer on chemical composition of groundwater was investigated from May 1991 to May 1994 in a farm land located West of Fukuoka city. It was ascertained that nitrate and dissolved oxygen concentrations in groundwater were greatly affected by the surface conditions of the farm land: paddy fields (April-August), vegetable fields (September-March), greenhouses (all seasons), fallow in farm land consolidation.
In the paddy fields, nitrate and dissolved oxygen concentrations decreased gradually from May, showing the minimum at the end of August. After the paddy fields were converted to vegetable fields, both concentrations began to increase, showing the maximum in March. This periodic variation of both concentrations is probably due to the change in the groundwater in view of the reduction or oxidizing conditions caused by the paddy field and vegetable field, respectively. In the land used for greenhouses, nitrate and dissolved oxygen concentrations in the groundwater were constant in high stage in all seasons. When the land was in consolidation, farming was stopped and the land was bare. During this period, since fertilizer was not used, the nitrate concentration was lower than that in the period the land had been used as vegetable field. On the other hand, the dissolved oxygen concentration was constant in high stage.

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Our study centers on providing tactile feedback in Mixed Reality (MR) environment. While most studies focus on the use of vibration and temperature to provide tactile feedback, vibration and temperature are not the only sensations a human can perceive. In this study, we focus on the psychophysical influence of MR visual stimulation on pain sensation. We conducted an experiment where we induce pain on the subject's forearm and display visual stimulation on a different position than where we induced the pain. We found out that the position where the subjects perceived pain, differs from the actual position according to the displayed visual stimulation.

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   Although there is much evidence showing that a posterior pituitary hormone oxytocin is involved in antinociception in the spinal dorsal horn, this action has not been yet examined fully. We examined the effects of oxytocin on (glutamatergic) excitatory and (GABAergic and glycinergic) inhibi­tory transmissions in spinal lamina II (substantia gelatinosa; SG) neurons which play a pivotal role in modulating nociceptive transmission to the CNS from the periphery. The blind whole–cell patch–clamp technique was applied to the SG neurons in the spinal cord slices of adult male rats. In 67％ of the neurons examined, oxytocin superfused for 3 min produced an inward current at −70 mV without a change in spontaneous excitatory transmission. Monosynaptically–evoked primary–afferent Aδ–fiber and C–fiber excitatory transmissions were also unaffected by oxytocin. The oxytocin current was resistant to a voltage–gated Na⁺–channel blocker tetrodotoxin (TTX), indicating a direct action of oxytocin which is not accompanied by an increase in neuronal activities. The oxytocin response was mimicked by an oxytocin–receptor agonist [Thr⁴,Gly⁷]–oxytocin (TGOT) and disappeared in the presence of an oxytocin–receptor antagonist [d(CH₂)₅¹,Tyr(Me)², Thr⁴,Orn⁸,des–Gly–NH₂⁹]–vasotocin (dVOT). The oxytocin current was inhibited by a phospholipase C inhibitor U–73122 and an IP₃–induced Ca²⁺–release inhibitor 2–aminoethoxydiphenyl borate. On the other hand, a protein kinase C inhibitor chelerythrine, a Ca²⁺–induced Ca²⁺–release inhibitor dantrolene and membrane–permeable dibutyryl cyclic–AMP did not affect the oxytocin activity. Current–voltage relationship for the oxytocin current reversed at negative potentials more than the equilibrium potential for K⁺ or around 0 mV. The oxytocin current was depressed in peak amplitude in high–K⁺, low–Na⁺ or Ba²⁺–containing Krebs solution. GABAergic and glycinergic spontaneous inhibitory postsynaptic currents were increased in frequency by oxytocin in a manner sensitive to TTX. These activities were mimicked by TGOT and inhibited by dVOT. It is concluded that oxytocin produces a membrane depolarization, probably due to Na⁺–permeability increase and/or K⁺–permeability decrease, being possibly mediated by phospholi­pase C and IP₃–induced Ca²⁺ release, which results in spontaneous inhibitory transmission enhancement, through oxytocin receptor activa­tion. This effect of oxytocin could contribute to its antinociceptive action.

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