N–acetyl–aspartyl–glutamate (NAAG) is the most prevalent and widely distributed peptide transmitter in the mammalian nervous system.NAAG acts as an agonist at metabotropic glutamate receptor 3 (mGluR3). Metabotropic GluRs have been identified as significant analgesic targets. NAAG is degraded to N–acetyl–aspartate (NAA) and glutamate by extra cellular peptidase which is named NAAG peptidase (also known as glutamate carboxypeptidase II (GCPII)). Glutamate, a metabolite of NAAG, may act as a neurotransmitter and activate glutamate receptors such as NMDA receptor and other type of mGluRs. Thus, it is impossible to examine the role of NAAG itself, if NAAG was administered. As a result, we examined the role of NAAG in the nocicep tive transmission by using NAAG peptidase inhibitors. In the present article, I showed the analgesic profile of NAAG peptidase inhibitors in the rat formalin model.
   NAAG peptidase inhibitor produced an analgesic effect when administered intravenously, locally, intrathecally, and intracerebroventricularly without any adverse effects. These analgesic effects were completely antagonized by intraperitoneal injection of LY341495, an mGluR3 antagonist. These data suggested that NAAG itself acts as analgesics by activating mGluR3. Next, I explored the site of action of NAAG peptidase inhibitor in the brain. Microinjection of NAAG peptidase inhibitor into the periaqueductal grey (PAG) contralateral, but not ipsilateral, to the side of formalin injection produced an analgesic effect and this effect was completely antagonized by LY341495. Microinjection of NAAG peptidase inhibitor into the rostral ventro medial medulla (RVM) produced analgesic action and this effect was completely antagonized by LY341495. These data suggested that PAG and RVM are the sites of action of NAAG peptidase inhibitor to produce an analgesic effect in the rat formalin model. In conclusion, these data strongly suggested that NAAG peptidase inhibitors are a target of new class analgesics.

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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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   Purpose: Neovessels and accompanying nerves are possible sources of pain. Previous work demonstrated that transcatheter arterial micro−emboliza­tion (TAME) for patients with adhesive capsulitis resulted in excellent pain relief. We hypothesized that abnormal neovessels also play an important role in nighttime shoulder pain with other conditions as well as adhesive capsulitis and that TAME can relieve pain.
   Material and Methods: TAME using imipenem ⁄ cilastatin sodium as an embolic agent proceeded to seventeen shoulders in sixteen patients, including adhesive capsulitis (n=6), subacromial impingement syndrome (n=7), rotator cuff tear without surgical indication (n=2), stiff shoulder (n=1), and chronic pain post scapula fracture (n=1). All patients had nighttime shoulder pain and previous conservative therapies applied for at least three months and persisted moderate−to−severe pain (Visual Analog Scale > 50 mm) before treatments. Adverse events, changes in Visual Analog Scale scores of night pain, and changes in self reporting sleep quality scores were assessed at 1 week and at 1, 3, and 6 months after the procedure.
   Results: Abnormal neovessels were identified in all cases. No major adverse events were related to the procedures. Transcatheter arterial micro− embolization rapidly decreased nighttime pain visual analog scale scores from 72 ± 7 mm to 42 ± 26 mm at 1 week after the procedure, with further improvement at 1, 3 and 6 months (28 ± 22 mm, 19 ± 24 mm, and 16 ± 23 mm respectively). Self reporting sleep quality scores and nighttime pain frequency improved and maintained for 6 months.
   Conclusion: Abnormal neovessels were observed in all patients. TAME of this lesion was feasible, effectively relieved unrelenting chronic night shoulder pain.

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