Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antinociceptive effect of rofecoxib, a preferential inhibitor of cyclooxygenase-2, was assessed in the pain-induced functional impairment model in the rat. Systemic administration of rofecoxib generated a dose-dependent antinociceptive effect in rats injected with uric acid into the knee joint of the right hindlimb in order to produce nociception. Ipsilateral intra-articular pretreatment with N(G)-L-nitro-arginine methyl ester (L-NAME, an inhibitor of nitric oxide (NO) synthesis), 1H-(1,2,4)-oxadiazolo (4,2-a)quinoxalin-1-one (ODQ, an inhibitor soluble guanylyl cyclase), and the ATP-sensitive potassium channel blocker glibenclamide reversed the antinociceptive effect of rofecoxib p.o. However, ipsilateral intra-articular pretreatment with L-arginine (a NO substrate), or 3-morpholino-sydnonimine-HCl (SIN-1, a non-enzymatic donor of NO), potentiated the antinociceptive effect induced by rofecoxib. The present results suggest that, in addition to cyclooxygenase-2 inhibition, the antinociceptive effect of rofecoxib could also involve activation of the L-arginine-NO-cyclic GMP (cGMP) pathway, followed by opening of ATP-sensitive K+ channels at the peripheral level.
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PMID:Participation of the L-arginine-nitric oxide-cyclic GMP-ATP-sensitive K+ channel cascade in the antinociceptive effect of rofecoxib. 1474 3

The present study was performed to investigate the antinociceptive response to the intracisternal administration of NMDA in the orofacial area. To achieve this purpose, the effects of NMDA injected intracisternally on the orofacial formalin test were monitored in freely moving rats. We also investigated underlying the mechanisms of NMDA-induced antinociceptive response. Experiments were carried out on 80 male SD rats and surgical procedures were performed under pentobarbital sodium (40 mg/kg, i.p.). Fifty microliters of 5% formalin was applied subcutaneously to the vibrissa pad without any restraining of the animals. For each animal, the number of noxious behavioral responses and the time spent grooming, rubbing, and/or scratching the facial region proximal to the injection site were recorded for nine successive 5-min intervals. The orofacial formalin responses showed two distinct phases separated by a time of relative inactivity. Intracisternal administration of NMDA produced intense scratching behavioral responses with dose related manner. NMDA injected intracisternally 30 min prior to formalin injection, however, inhibited noxious behavioral responses produced by a formalin injection significantly. Pretreatment with naloxone 20 min prior to NMDA injection abolished the inhibition of number of scratches and the duration of scratching produced by the intracisternal injection of NMDA in the late phase. Pretreatment with L-NAME, NO synthesis inhibitor, however, did not affect the antinociceptive response produced by NMDA injected intracisternally. These results suggest that NMDA injected intracisternally produces brief pain behavioral responses and also produces delayed antinociceptive effects in the orofacial formalin test. The opioid pathway seems to be involved in the NMDA-induced antinociception in the orofacial area.
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PMID:Intracisternal NMDA produces analgesia in the orofacial formalin test of freely moving rats. 1509 57

Snakebites constitute a serious public health problem in Central and South America, where species of the lancehead pit vipers (genus Bothrops) cause the majority of accidents. Bothrops envenomations are very painful, and this effect is not neutralized by antivenom treatment. Two variants of secretory phospholipases A2 (sPLA2), corresponding to Asp49 and Lys49 PLA2s, have been isolated from Bothrops asper venom. These sPLA2s induce hyperalgesia in rats following subcutaneous injection. However, venom in natural Bothrops bites is frequently delivered intramuscularly, thereby potentially reaching peripheral nerve bundles. Thus, the present series of experiments tested whether these sPLA2s could exert pain-enhancing effects following administration around healthy sciatic nerve. Both were found to produce mechanical allodynia ipsilateral to the injection site; no thermal hyperalgesia was observed. As no prior study has examined potential spinal mechanisms underlying sPLA2 actions, a series of anatomical and pharmacological studies were performed. These demonstrated that both sPLA2s produce activation of dorsal horn astrocytes and microglia that is more prominent ipsilateral to the site of injection. As proinflammatory cytokines and nitric oxide have each been previously implicated in spinally mediated pain facilitation, the effect of pharmacological blockade of these substances was tested. The results demonstrate that mechanical allodynia induced by both sPLA2s is blocked by interleukin-1 receptor antagonist, anti-rat interleukin-6 neutralizing antibody, the anti-inflammatory cytokine interleukin-10, and a nitric oxide synthesis inhibitor (L-NAME). As a variety of immune cells also produce and release sPLA2s during inflammatory states, the data may have general implications for the understanding of inflammatory pain.
Pain 2004 Mar
PMID:Snake venom phospholipase A2s (Asp49 and Lys49) induce mechanical allodynia upon peri-sciatic administration: involvement of spinal cord glia, proinflammatory cytokines and nitric oxide. 1510 22

It has become clear that spinal cord glia (microglia and astrocytes) importantly contribute to the creation of exaggerated pain responses. One model used to study this is peri-spinal (intrathecal, i.t.) administration of gp120, an envelope protein of HIV-1 known to activate glia. Previous studies demonstrated that i.t. gp120 produces pain facilitation via the release of glial proinflammatory cytokines. The present series of studies tested whether spinal nitric oxide (NO) contributes to i.t. gp120-induced mechanical allodynia and, if so, what effect NO has on spinal proinflammatory cytokines. gp120 stimulation of acutely isolated lumbar dorsal spinal cords released NO as well as proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta (IL1), interleukin-6 (IL6)), thus identifying NO as a candidate mediator of gp120-induced behavioral effects. Behaviorally, identical effects were observed when gp120-induced mechanical allodynia was challenged by i.t. pre-treatment with either a broad-spectrum nitric oxide synthase (NOS) inhibitor (L-NAME) or 7-NINA, a selective inhibitor of NOS type-I (nNOS). Both abolished gp120-induced mechanical allodynia. While the literature pre-dominantly documents that proinflammatory cytokines stimulate the production of NO rather than the reverse, here we show that gp120-induced NO increases proinflammatory cytokine mRNA levels (RT-PCR) and both protein expression and protein release (serial ELISA). Furthermore, gp120 increases mRNA for IL1 converting enzyme and matrix metalloproteinase-9, enzymes responsible for activation and release of proinflammatory cytokines.
Pain 2004 Aug
PMID:HIV-1 gp120 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-I (nNOS). 1528 92

The present study provides an important implication for the management of chronic neuropathic pain, focusing on prostaglandin (PG) and nitric oxide (NO) in the spinal cord. To determine if spinally administered cyclooxygenase (COX) inhibitor or nitric oxide synthase (NOS) inhibitor had preemptive analgesia on thermal hypersensitivity induced by chronic constrictive nerve injury, Sprague-Dawley rats were chronically implanted with an intrathecal (i.t.) catheter. The left sciatic nerve was loosely ligated with 2-mm polyethylene tubing to produce painful mononeuropathy. Animals received tenoxicam (7.5, 15 or 30 micromol/10 microl, i.t.), NS-398 (15 or 30 micromol), or L-NAME (30, 150 or 300 micromol) immediately before the nerve injury, followed by daily injection extending into the four postoperative days. The hindpaw was immersed into a hot (42 degrees C, 44 degrees C and 46 degrees C) or cold (10 degrees C) water bath. The paw immersion test revealed significant thermal hyperalgesia and allodynia 5 day after nerve injury in vehicle control animals. Tenoxicam (7.5, 15 or 30 micromol) or L-NAME (30, 150 or 300 micromol) dose-dependently attenuated hyperalgesia and allodynia. Equimolar dose of NS-398 (15 or 30 micromol) also diminished these nociceptive behaviors. Higher dose of either drug primarily produced longer duration of inhibition. The inhibitory effect of tenoxicam (30 micromol) on hyperalgesia was more effective than that of an equimolar dose of NS-398 or L-NAME. These results demonstrated that intrathecally administered COX inhibitor or NOS inhibitor provides preemptive analgesia on thermal hypersensitivity following chronic constrictive nerve injury in rats.
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PMID:Preemptive effects of intrathecal cyclooxygenase inhibitor or nitric oxide synthase inhibitor on thermal hypersensitivity following peripheral nerve injury. 1536 58

Diabetic neuropathy is one of the most frequent peripheral neuropathies associated with hyperalgesia and hyperesthesia. Besides alteration in the levels of neurotransmitter, alteration in the neuronal nitric oxide synthase (nNOS) is a key factor in the pathogenesis of diabetic neuropathy. The present study was aimed at evaluating the role of PDE-5 inhibitor on nociception in streptozotocin-induced diabetes in animal models of nociception (writhing assay in mice and paw hyperalgesia test in rats). Diabetic animals showed a significant decrease in pain threshold as compared to non-diabetic animals in both tests, indicating diabetes induced hyperalgesia in mice and rats. The PDE-5 inhibitor, sildenafil, significantly increased the pain threshold in both diabetic and non-diabetic animals. However, L-NAME, a non-specific NOS inhibitor and methylene blue (MB), a guanylate cyclase inhibitor blocked the antinociceptive effect. The per se administration of L-NAME or MB augmented the hyperalgesic response in diabetic animals with little or no effect in non-diabetic animals, indicating the alteration of NO-cGMP pathway in diabetes. The results in the present study demonstrate that the decreased nNOS-cGMP system may play a crucial role in the pathogenesis of diabetic neuropathy.
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PMID:Modulatory effect of the PDE-5 inhibitor sildenafil in diabetic neuropathy. 1545 68

Accidents caused by the venomous fish Thalassophryne nattereri are characterized by edema, intense pain and necrosis at the site of the sting. This study assessed the nociceptive and edematogenic activities of T. nattereri venom after injection into the mouse hindpaw and determination of the paw licking duration and weight. Subplantar injections of the venom (0.1-6 microg) induced a dose-related increase of the paw licking time and paw swelling with maximal values at 3 microg (209.5 +/- 57.5 s and 135.0 +/- 6.8 mg, respectively). Pretreatment of mice with either indomethacin (10 mg/kg, i.p.), a cyclooxygenase inhibitor, dexamethasone (1 mg/kg, s.c.), a steroid anti-inflammatory agent, cyproheptadine (1 mg/kg, i.p.), antagonist of serotonin receptors or L-NAME (100 mg/kg, s.c.), inhibitor of nitric oxide syntase, did not affect the venom-induced nociceptive and edematogenic responses. Injection of the opioid analgesic fentanyl (0.1 mg/kg, s.c.) reduced the paw licking time induced by 1 microg venom by 84% of control, without affecting the paw swelling. Both nociceptive and edematogenic responses were reduced after treatment with a specific tissue kallikrein inhibitor (TKI, 100 mg/kg, i.p.) by 78% and 24% from control values, respectively. Administration of a specific plasma kallikrein inhibitor (PKSI(527,) 100 mg/kg, s.c.) did not affect the venom-induced nociceptive response, but it decreased the paw edema by 15% from control. After injection of the angiotensin-converting enzyme inhibitor captopril (100 mg/kg, i.p.) the venom-induced nociceptive end edematogenic responses were increased by two-fold. The role of kallikreins possibly present in the venom was further assessed by hydrolysis of human kininogen and kininogen-derived synthetic peptides, showing the release of kallidin (Lys-bradykinin). The hydrolysis was inhibited by metal chelating agents but not by serino-, aspartyl- or cysteino-proteinase inhibitors. The data suggest that a protease with tissue-kallikrein-like activity plays a major role in nociception and edema induced by T. nattereri venom and this should be considered to achieve efficient treatments for human accidents with this venom.
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PMID:Kininogenase activity of Thalassophryne nattereri fish venom. 1549 5

It has been considered that tramadol, a centrally acting analgesic, shows its effect via opiatergic, noradrenergic, and serotonergic systems. It has a low affinity for opioid receptors, and its effect can be partly blocked by naloxone. Since the noradrenergic and serotonergic mechanisms are still unknown, other systems which are associated with pain and analgesia may have a role on the antinociceptive effect of tramadol. The aim of this study was to evaluate the effects of K+ channels and nitrergic systems on the antinociceptive action of tramadol. The antinociceptive effects of tramadol were determined in mice by the hot plate test. To examine the effects of K+ channels and the nitrergic system nonspecific voltage-dependent K+ channel blockers 4-aminopyridine (4-AP) and tetraethylammonium (TEA), nitric oxide (NO) precursor L-arginine, and the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) were used. Our results indicated that 4-AP, TEA, and L-arginine reduced the antinociceptive effect of tramadol. However, L-NAME augmented the antinociceptive effect of tramadol. The reduction of the effects of tramadol by L-arginine was reversed by L-NAME. The results of our study suggest that nonspecific voltage-dependent K+ channels and nitrergic system have a role on the antinociceptive effect of tramadol in mice hot plate test.
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PMID:Involvement of potassium channels and nitric oxide in tramadol antinociception. 1565 82

Glutamate is a major excitatory neurotransmitter in primary afferent terminals and is critical for normal spinal excitatory synaptic transmission. However, little is known about the regulation of synaptically released glutamate in the spinal cord under physiologic conditions. The sodium-dependent, high-affinity glutamate transporters are the primary mechanism for the clearance of synaptically released glutamate. In the present study, we found that intrathecal injection of glutamate transporter blockers DL-threo-beta-benzyloxyaspartate (TBOA) and dihydrokainate produced significant and dose-dependent spontaneous nociceptive behaviors, such as licking, shaking, and caudally directed biting, phenomena similar to the behaviors caused by intrathecal glutamate receptor agonists. Intrathecal TBOA also led to remarkable hypersensitivity in response to thermal and mechanical stimuli. These behavioral responses could be significantly blocked by intrathecal injection of the NMDA receptor antagonists MK-801 and AP-5, the non-NMDA receptor antagonist CNQX or the nitric oxide synthase inhibitor L-NAME. In vivo microdialysis analysis showed short-term elevation of extracellular glutamate concentration in the spinal cord after intrathecal injection of TBOA. Furthermore, topical application of TBOA on the dorsal surface of the spinal cord resulted in a significant elevation of extracellular glutamate concentration demonstrated by in vivo glutamate voltametry. The present study indicates that defective spinal glutamate uptake caused by inhibition of glutamate transporters leads to excessive glutamate accumulation in the spinal cord. The latter results in persistent over-activation of synaptic glutamate receptors, producing spontaneous nociceptive behaviors and sensory hypersensitivity. Our results suggest that glutamate uptake through spinal glutamate transporters is critical for maintaining normal sensory transmission under physiologic conditions.
Pain 2005 May
PMID:Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord. 1583 70

1. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is a COX-inhibiting nitric oxide donor that inhibits COX-1 and COX-2. It is as effective as naproxen in models of pain and inflammation, but causes less gastroduodenal damage. Nitric oxide (NO) is generated from AZD3582 in vitro, and this study sought to show that the drug donates NO in vivo. 2. In anaesthetised male New Zealand white rabbits, the endogenous NO concentration in exhaled air was reduced by N(G)-nitro-L-arginine methyl ester (L-NAME) (30 mg kg(- 1) i.v.) from 33.5+/-1.0 ppb (mean+/-s.e.m.; n=6 per group) to 3.0+/-1.0 ppb, while increasing blood pressure and reducing heart rate. AZD3582 (0.2, 0.6, 2.0 or 6.0 micromol kg(- 1) min(- 1)) given 30 min after L-NAME increased the concentration of NO in exhaled air (P<0.05), decreased blood pressure and increased heart rate in a dose-dependent manner versus L-NAME control values. The peak mean NO concentration obtained was 44+/-8.0 ppb. 3. In in situ-perfused rabbit lungs, L-NAME (185 micromol l(- 1)) reduced the NO concentration in exhaled air from 106+/-13 to 4.0+/-0.4 ppb (n=5). Addition of AZD3582 (6 micromol min(- 1)) to the perfusate produced an initial rapid increase in the NO concentration in exhaled air, followed by a sustained, but lower plateau. Infusion of L-NAME increased, and AZD3582 decreased, pulmonary arterial pressure. 4. In both anaesthetised rabbits and in the perfused lungs, brief periods of hypoxia increased NO concentrations generated by AZD3582. 5. We conclude that, in rabbits, AZD3582 donates NO in vivo with characteristics similar to those reported for nitroglycerin and isosorbide nitrates
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PMID:Direct gas measurements indicate that the novel cyclooxygenase inhibitor AZD3582 is an effective nitric oxide donor in vivo. 1585 32


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