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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In spite of prominent progress in basic pain research, neuropathic pain remains a significant medical problem, because it is often poorly relieved by conventional analgesics. Thus this situation encourages us to make more sophisticated efforts toward the discovery of new analgesics. We previously showed that i.t. administration of acromelic acid-A (ACRO-A), a Japanese mushroom poison, provoked prominent tactile pain (allodynia) at an extremely low dose of 1 fg/mouse. In the present study we synthesized ACRO-A analogues (2S,3R,4R)-3-carboxymethyl-4-phenoxypyrrolidine-2-carboxylic acid (POPA-2) and (2S,3R,4R)-3-carboxymethyl-4-(phenylthio)pyrrolidine-2-carboxylic acid (PSPA-1) chemically and examined their ability to induce allodynia in conscious mice. Whereas POPA-2 induced allodynia at extremely low doses from 1 to 100 fg/mouse, similar to ACRO-A, PSPA-1 did not induce allodynia; rather, it inhibited the ACRO-A-induced allodynia with an ID(50) value (95% confidence limits) of 2.19 fg/mouse (0.04-31.8 fg/mouse). Furthermore, PSPA-1 relieved neuropathic pain produced by L5 spinal nerve transection on day 7 after the operation in a dose-dependent manner from 1 to 100 pg/mouse. In contrast, it did not affect thermal or mechanical nociception or inflammatory pain. PSPA-1 reduced the increase in neuronal nitric oxide synthase activity in the spinal cord of neuropathic pain mice assessed by NADPH-diaphorase histochemistry and blocked the allodynia induced by N-methyl-d-aspartate. These results demonstrate that PSPA-1 may represent a novel class of anti-allodynic agents for neuropathic pain acting by blocking the glutamate-nitric oxide pathway.
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PMID:A synthetic kainoid, (2S,3R,4R)-3-carboxymethyl-4-(phenylthio)pyrrolidine-2-carboxylic acid (PSPA-1) serves as a novel anti-allodynic agent for neuropathic pain. 1782 64

Peripheral nerve lesion-induced production of neuronal nitric oxide synthase (nNOS) was implicated to influence a range of postaxotomy processes necessary for neuronal survival and nerve regeneration (Zochodne et al., Neuroscience, 91:1515-1527, 1999; Keilhoff et al., Journal of Chemical Neuroanatomy, 24:181-187, 2002, Nitric Oxide, 10:101-111, 2004). Protein-protein interactions represent an important mechanism in the control of NOS spatial distribution or activity (Alderton et al., Biochemical Journal, 357:593-615, 2001; Dedio et al., FASEB Journal, 15:79-89, 2001; Zimmermann et al., Proceedings of the National Academy of Sciences, 99:17167-17172, 2002). As one of the nNOS-binding proteins, nNOS-interacting DHHC domain-containing protein with dendritic mRNA (NIDD) has recently been identified to increase nNOS enzyme activity by targeting nNOS to the synaptic plasma membrane in a postsynaptic density protein 95/discs-large/zona occlusens-1 domain dependent manner (Saitoh et al., Journal of Biological Chemistry, 279:29461-29468, 2004). In this paper, we established a rat model with peripheral axotomy to investigate the gene expression patterns of NIDD in neural tissues using TaqMan quantitative real-time polymerase chain reaction and in situ hybridization combined with immunofluorescence. It revealed that NIDD mRNA was upregulated after sciatic nerve transection with the similar expressing styles as that of the nNOS in the injured nerves, corresponding dorsal root ganglia, and lumbar spinal cord. These findings imply that NIDD may be involved in the different pathological conditions including nerve regeneration, neuron loss or survival, and even pain process, possibly via regulating the enzyme nNOS activity.
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PMID:Effect of peripheral axotomy on gene expression of NIDD in rat neural tissues. 1787 65

Nitric oxide and nitric oxide synthases are key players in synaptic plasticity events in spinal cord (SC), which underlies the chronic pain states. To date, little is known about the molecular mechanisms regulating the activity of nitric oxide synthases in nociceptive systems. The present study was aimed at the determination of the gene expression of nNOS-interacting DHHC domain-containing protein with dendritic mRNA (NIDD), a recently identified protein regulating nNOS enzyme activity, in rat SC and dorsal root ganglia (DRG) and studying its regulation in states of nociceptive hypersensitivity in a rat model of neuropathic or inflammatory pain. It was found that NIDD mRNA was predominantly expressed in nociceptive primary neurons and in neurons of the spinal dorsal horn (DH) and the number of NIDD-positive neurons in the corresponding DRG or SC increased significantly following induction of chronic hyperalgesia. Meanwhile, remarkable changes of nNOS were detected under such pain conditions. Our data suggest a potential role for NIDD in the maintenance of thermal pain hypersensitivity possibly via regulating the nNOS activity.
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PMID:Altered gene expression of NIDD in dorsal root ganglia and spinal cord of rats with neuropathic or inflammatory pain. 1789 3

N-methyl-D-aspartate receptor subunit 2B (NR2B) and neuronal nitric oxide synthase (nNOS) play important roles in the mechanism of neuropathic pain. To elucidate how glucocorticoids affect this mechanism, we studied the effects of intrathecal (it) injection of prednisolone acetate (PA) on a nociceptive stimulus and the changes of nNOS and NR2B subunit expression in the spinal dorsal horn of Sprague Dawley rats following chronic compression of the dorsal root ganglia (CCD). Paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measured for 15 days postoperatively. An it injection of PA (2.0 mg/kg) every 3 days for postoperative days 1 to 15 inhibited the thermal hyperalgesia and tactile allodynia of CCD rats. Chronic compression of the dorsal root ganglia induced time-dependent upregulation of nNOS and NR2B subunits of N-methyl-D-aspartate receptor within the spinal cord dorsal horn ipsilateral to CCD. Both upregulations were significantly diminished by it administration of PA (2.0 mg/kg), but not by lower doses of PA (0.5 or 1.0 mg/kg). The results suggest that PA upregulation of neuronal nitric oxide synthase and NR2B subunit expression in the spinal dorsal horn contributes to PA inhibition of hyperalgesia induced by chronic compression of dorsal root ganglia.
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PMID:Effects of intrathecal injection of prednisolone acetate on expression of NR2B subunit and nNOS in spinal cord of rats after chronic compression of dorsal root ganglia. 1800 Feb 92

Tramadol is a centrally acting analgesic which is used mainly for the treatment of moderate or severe pain. It is a synthetic opioid in the aminocyclohexanol group that binds weakly to micro-opioid receptors. Since it has been suggested that both opioid and monoaminergic systems play a role in depressive disorders, tramadol has been studied in the forced swimming test (FST). The present study was designed to explore the antidepressant activity of tramadol in rat FST and its possible mechanisms of action. The involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of tramadol was investigated. Treatment with tramadol, given (30 min earlier) by oral route (p.o.) at the doses of 10, 20 and 40 mg/kg, decreased immobility time in the FST. Pretreatment of rats with L-arginine (250 mg/kg, intraperitoneal, i.p., a nitric oxide precursor) or sildenafil (5 mg/kg, i.p., a phosphodiesterase 5 inhibitor, PDE5) significantly reversed the reduction in immobility time elicited by tramadol (20 mg/kg, p.o.) in the FST. Treatment of animals with a sub-effective dose of tramadol (5 mg/kg, p.o.) produced a synergistic antidepressant-like effect with N(G)-nitro-L-arginine (L-NNA, 3 mg/kg, i.p., an inhibitor of nitric oxide synthase) or with 7-nitroindazole (7-NI, 9 mg/kg i.p., a specific neuronal nitric oxide synthase inhibitor) in the FST. Pretreatment of animals with methylene blue (3.75 mg/kg i.p., an inhibitor of NO synthase and soluble guanylate cyclase - sGC) or (1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one) (ODQ, 2 mg/kg, i.p., a specific inhibitor of sGC) significantly caused a synergistic effect with a sub-effective dose of tramadol (5 mg/kg, p.o.) in the FST. In the present study, different doses of tramadol and the combination with the L-arginine-NO-cGMP pathway modulators had no effect on the locomotor activity of rats in the open-field test. Thus, our findings suggest that the acute administration of tramadol produces antidepressant-like effect in the rat FST by a mechanism that involves the inhibition of L-arginine-NO-cGMP pathway.
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PMID:Involvement of L-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of tramadol in the rat forced swimming test. 1877 34

The purpose of this study was to investigate the effect of cyclooxygenase (COX) inhibitors and nitric oxide synthase (NOS) inhibitors on the development of vincristine (VIN)-induced hyperalgesia. Indomethacin (IND) and celecoxib (CEX) were used as relatively selective inhibitors of COX-1 and COX-2, respectively. NOS inhibitors included the nonspecific inhibitor NG-nitro-Larginine (L-NOArg) and L-N6-(1-iminoethyl)lysine (L-NIL), which preferentially acts on inducible NOS, as well as 7-nitroindazole (7-NI), which is a relatively specific neuronal NO synthase inhibitor. Both IND and CEX markedly suppressed hyperalgesia, whereas all three NOS inhibitors prevented the development of hyperalgesia due to VIN administration. The results of this study suggest participation of COX-1 and COX-2 as well as iNOS and nNOS in the transmission of pain stimuli in VIN-induced hyperalgesia.
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PMID:Effect of cyclooxygenase and nitric oxide synthase inhibitors on vincristine induced hyperalgesia in rats. 1906 21

Nitric oxide, which has been implicated in the development of hyperalgesia in the spinal system, has not been systematically studied in the trigeminal system, especially in the context of inflammatory muscle pain condition. In this study, we investigated the functional role of centrally released nitric oxide in the pathogenesis of orofacial muscle pain. Specifically, we examined the contribution of neuronal, inducible and endothelial nitric oxide synthases, nNOS, iNOS and eNOS, respectively, in mediating masseter hypersensitivity under acute inflammatory condition. Time-dependent changes in nNOS, iNOS and eNOS protein expression in the subnucleus caudalis (Vc) were assessed following capsaicin injection in the masseter muscle of male Sprague Dawley rats. The expression of all three nitric oxide synthases was significantly up-regulated 30-60 min following capsaicin stimulation, which paralleled the time course of the development of capsaicin-induced masseter hypersensitivity. Pretreatment with each NOS inhibitor significantly attenuated the masseter hypersensitivity. These data showed that all three NOS in the Vc are functionally important for the development of craniofacial muscle hyperalgesia and suggest that the three NOS are closely orchestrated to regulate the level of nitric oxide under normal and pathologic conditions.
Eur J Pain 2009 Oct
PMID:Involvement of neuronal, inducible and endothelial nitric oxide synthases in capsaicin-induced muscle hypersensitivity. 1908 37

Evidence for the important role of the potent oxidant peroxynitrite in peripheral diabetic neuropathy and neuropathic pain is emerging. This study evaluated the contribution of neuronal nitric oxide synthase (nNOS) to diabetes-induced nitrosative stress in peripheral nerve and dorsal root ganglia, and peripheral nerve dysfunction and degeneration. Control and nNOS-/- mice were made diabetic with streptozotocin, and maintained for 6 weeks. Peroxynitrite injury was assessed by nitrotyrosine and poly(ADP-ribose) immunoreactivities. Peripheral diabetic neuropathy was evaluated by measurements of sciatic motor and hind-limb digital sensory nerve conduction velocities, thermal algesia, tactile allodynia, and intraepidermal nerve fiber density. Control nNOS-/- mice displayed normal motor nerve conduction velocity and thermal response latency, whereas sensory nerve conduction velocity was slightly lower compared with non-diabetic wild-type mice, and tactile response threshold and intraepidermal nerve fiber density were reduced by 47 and 38%, respectively. Both diabetic wild-type and nNOS-/- mice displayed enhanced nitrosative stress in peripheral nerve. In contrast to diabetic wild-type mice, diabetic nNOS-/- mice had near normal nitrotyrosine and poly(ADP-ribose) immunofluorescence in dorsal root ganglia. Both diabetic wild-type and nNOS-/- mice developed motor and sensory nerve conduction velocity deficits and thermal hypoalgesia although nNOS gene deficiency slightly reduced severity of the three disorders. Tactile response thresholds were similarly decreased in control and diabetic nNOS-/- mice compared with non-diabetic wild-type mice. Intraepidermal nerve fiber density was lower by 27% in diabetic nNOS-/- mice compared with the corresponding non-diabetic group, and by 20% in diabetic nNOS-/- mice compared with diabetic wild-type mice. In conclusion, nNOS is required for maintaining the normal peripheral nerve function and small sensory nerve fibre innervation. nNOS gene deficiency does not protect from development of nerve conduction deficit, sensory neuropathy and intraepidermal nerve fiber loss.
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PMID:Peripheral neuropathy in mice with neuronal nitric oxide synthase gene deficiency. 1936 Mar 14

The role of central and peripheral neuronal nitric oxide synthase (nNOS) splice variants in the development of inflammatory hyperalgesia was investigated using the formalin test. Supraspinal administration of the NOS inhibitor NOArg lowered both the first and second phase of the formalin response. An oligodeoxynucleotide targeting four nNOS isoforms given supraspinally also reduced the formalin response of both phases. Supraspinal antisense mapping suggested that this effect results from the nNOS-1 splice variant, implying that nNOS-1 is important in mediating formalin pain. At the spinal level, antisense mapping suggested a role of both the nNOS-1 and the nNOS-beta variants in producing formalin pain. Conversely, an antisense selective against nNOS-2 had an opposing effect against the first phase, increasing its intensity. This result, which was similar to prior studies examining opioid actions, implies that endogenous nNOS-2 activity acted to minimize pain perception. Locally in the foot, arginine, the precursor for NO, increased the phase II response at low doses while higher doses reduced the response. This complex biphasic response suggested opposing NOS actions. Local antisense mapping again showed that nNOS-1 is involved in producing phase II of the formalin response while nNOS-2 had an opposite effect similar to that seen spinally. Finally, downregulation of nNOS-1 by antisense prevented tolerance to morphine in both the tail-flick and the formalin test. Together, these observations illustrate the complexity of nNOS in pain perception and the existence of opposing nNOS systems likely due to splice variants of nNOS.
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PMID:Opposing actions of neuronal nitric oxide synthase isoforms in formalin-induced pain in mice. 1954 48

Intrathecal (i.t.) injection of morphine-3-glucuronide (M3G), a major metabolite of morphine without analgesic actions, produces a severe hindlimb scratching followed by biting and licking in mice. The pain-related behavior evoked by M3G was inhibited dose-dependently by i.t. co-administration of tachykinin NK(1) receptor antagonists, sendide, [D-Phe(7), D-His(9)] substance P(6-11), CP-99994 or RP-67580 and i.t. pretreatment with antiserum against substance P. The competitive NMDA receptor antagonists, D-APV and CPP, the NMDA ion-channel blocker, MK-801 or the competitive antagonist of the polyamine recognition site of NMDA receptor ion-channel complex, ifenprodil, produced inhibitory effects on i.t. M3G-evoked nociceptive response. The NO-cGMP-PKG pathway, which involves the extracellular signal-regulated kinase (ERK), has been implicated as mediators of plasticity in several pain models. Here, we investigated whether M3G could influence the ERK activation in the NO-cGMP-PKG pathway. The i.t. injection of M3G evoked a definite activation of ERK in the lumbar dorsal spinal cord, which was prevented dose-dependently by U0126, a MAP kinase-ERK inhibitor. The selective nNOS inhibitor N(omega)-propyl-l-arginine, the selective iNOS inhibitor W1400, the soluble guanylate cyclase inhibitor ODQ and the PKG inhibitor KT-5823 inhibited dose-dependently the nociceptive response to i.t. M3G. In western blotting analysis, inhibiting M3G-induced nociceptive response using these inhibitors resulted in a significant blockade of ERK activation induced by M3G in the spinal cord. Taken together, these results suggest that activation of the spinal ERK signaling in the NO-cGMP-PKG pathway contributes to i.t. M3G-evoked nociceptive response.
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PMID:Spinal ERK activation via NO-cGMP pathway contributes to nociceptive behavior induced by morphine-3-glucuronide. 1958 34


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