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)

Interferential current (IFC) was suggested to improve the skin manifestations of psoriasis vulgaris, possibly by enhancing the intracellular concentration of cyclic AMP. We assessed the efficacy of IFC on psoriatic arthritis (PsA). Nine consecutive patients were analyzed at baseline and after 16 weeks of IFC therapy. Bipolar IFC was applied twice daily to hands, feet plus all affected joints. IFC improved SF-36 assessed body pain, but not other SF-36 subscales. Morning stiffness, tender joint counts, and physician assessed disease activity improved. In contrast, visual analogue scale assessed pain, CRP and ESR measurements were unchanged. MRI of the most affected hand or foot documented a tendency towards worsened tendinitis, soft tissue swelling, and new joint space narrowing and erosions. Bone scintigraphy showed a trend towards deterioration. New joints became inflamed within treated sites. Thus IFC has analgesic effects in PsA, but does not have a satisfactory disease modifying effect.
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PMID:Analgesic and disease modifying effects of interferential current in psoriatic arthritis. 1643 86

Rats given moderate spinal cord injury (SCI) display increases in the expression of the activated form of the transcription factor cyclic AMP responsive element binding protein (CREB) in spinal segments of dermatomes corresponding to permanent mechanical allodynia, a model of chronic central neuropathic pain (CNP; (Crown, E.D., Ye, Z., Johnson, K.M., Xu, G.Y., McAdoo, D.J., Westlund, K.N., Hulsebosch, C.E., 2005. Upregulation of the phosphorylated form of CREB in spinothalamic tract cells following spinal cord injury: relation to central neuropathic pain. Neurosci. Lett. 384, 139-144)). Given that not all rats that receive moderate SCI develop CNP, the current study was designed to further analyze changes in persistent CREB activation and in the activation state of upstream intracellular signaling cascades (e.g., mitogen-activated protein kinases [MAPKs]) in populations of rats that receive SCI and weeks later develop CNP and rats that receive SCI but do not develop CNP. The results indicate that activated kinases such as pERK 1/2, p-p38 MAPK, but not pJNK, are upregulated in injured rats that develop CNP as compared to injured rats that fail to develop CNP. In addition, the current results replicated our previous finding that activated CREB is upregulated following SCI, however, only in SCI rats that developed CNP. Taken together, these results indicate that activation of intracellular signaling cascades traditionally associated with long-term potentiation and memory is associated with the expression of chronic CNP following SCI.
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PMID:Increases in the activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury. 1647 24

A transcription factor known as cyclic AMP response element-binding protein has been shown to be involved in the central sensitization in neuropathic pain and inflammation pain. The present study examined the roles of cyclic AMP response element-binding protein and of the phosphorylated cyclic AMP response element-binding protein in the maintenance of mechanical and cold allodynia induced by a neuropathic pain model, "spared nerve injury," in rats. First, the results of immunohistochemical study showed that phosphorylated cyclic AMP response element-binding protein, but not cyclic AMP response element-binding protein, increased bilaterally in the spinal dorsal horn 14 days following spared nerve injury, indicating a possible contribution of phosphorylated cyclic AMP response element-binding protein in spared nerve injury. Second, chronic intrathecal application of cyclic AMP response element-binding protein antisense oligodeoxynucleotide with three doses (10 microg/day, 20 microg/day and 40 microg/day) for 5 days demonstrated that the higher doses (20 and 40 microg) significantly attenuated both mechanical (bilaterally) and cold (ipsilaterally) allodynia, compared with sense oligodeoxynucleotide and the lower dose (10 microg). Western blot results showed that the alleviation in intensity of behavioral performance was accompanied by a significant reduction of total cyclic AMP response element-binding protein and phosphorylated cyclic AMP response element-binding protein in the spinal dorsal horn. Moreover, there were no differences in cyclic AMP response element-binding protein and phosphorylated cyclic AMP response element-binding protein between ipsilateral and contralateral dorsal horns. Our data demonstrate a close association between the expression of behavioral hypersensitivity and cyclic AMP response element-binding protein activation in the spinal dorsal horn following spared nerve injury, supporting the notion that phosphorylated cyclic AMP response element-binding protein may play an important role in the maintenance of chronic neuropathic pain.
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PMID:Dose-related antiallodynic effects of cyclic AMP response element-binding protein-antisense oligonucleotide in the spared nerve injury model of neuropathic pain. 1651 39

Chronic opioid-induced analgesic tolerance remains a major obstacle to improving clinical management of moderate to severe chronic pain. Our understanding of the underlying mechanisms for opioid tolerance is only partially understood at present. In this study, we investigated the effects of chronic morphine on GABA(A) receptor-mediated synaptic transmission, a major opioid target for pain inhibition, and the behavioral role of GABA synaptic transmission in the development of morphine tolerance. In the nucleus raphe magnus (NRM), a critical brainstem site for opioid analgesia, the GABA(A) receptor-mediated inhibitory postsynaptic current (IPSC) was significantly increased in NRM neurons kept in a morphine-tolerant state from chronic morphine-treated rats. The potency of cAMP analogs for enhancing the GABA IPSC was also enhanced. The protein kinase A (PKA) inhibitor H89 reversed the chronic morphine-induced synaptic adaptation in GABA IPSCs. Behaviorally, a low dose of GABA(A) receptor antagonist bicuculline microinjected into the NRM, ineffective alone, blocked morphine antinociception in control rats, but failed to do so in morphine-tolerant rats. With chronic treatment through daily NRM microinjections, bicuculline augmented the development of morphine tolerance, whereas the GABA(A) receptor agonist muscimol or H89 significantly attenuated the development of morphine tolerance. These results suggest that chronic morphine increases GABA synaptic activity through upregulation of the AMP system in morphine-tolerant NRM neurons and that while chronic GABA(A) receptor antagonism in the NRM augments morphine tolerance, chronic activation of NRM GABA(A) receptors or PKA inhibition reduces morphine tolerance with increased analgesic efficacy of chronic morphine.
Pain 2006 May
PMID:Contribution of brainstem GABA(A) synaptic transmission to morphine analgesic tolerance. 1652 6

P2X2 and P2X3 receptors expressed in mammalian sensory neurons participate in nociception. Cannabinoid receptors modulate nociceptive processing in various models of pain. They are also expressed in nociceptive sensory neurons. We have examined the effect of cannabinoids on the slow P2X2 and P2X2/3 receptors in the cells isolated from nodosal and dorsal root ganglia of rat. The study was carried out by means of the whole-cell patch clamp and rapid superfusion methods. We have found that both endogenous and synthetic cannabinoids (anandamide, WIN55,212-2, and (R)-(+)-methanandamide) inhibit the slow response to ATP mediated by P2X2 and P2X2/3 receptors in a majority of tested neurons. This inhibition was significant but only partial: anandamide (0.5-1 microM) inhibited the response to 51+/-21% of control. In the remaining minority of tested neurons, the response was transiently facilitated. The effect of cannabinoids appears to be mediated via cannabinoid CB(1) receptors: it was reversibly inhibited by selective CB(1) antagonist, SR141716A (10 microM). Introduction of cyclic AMP (0.5 mM) into the cell potently facilitated the inhibitory effect of cannabinoids: the ATP-activated current was inhibited to 13+/-10% of control. These data indicate that cannabinoids may inhibit nociceptive responses produced by P2X receptors.
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PMID:The agonists for nociceptors are ubiquitous, but the modulators are specific: P2X receptors in the sensory neurons are modulated by cannabinoids. 1674 55

Integral to neuropathic pain is a reciprocal interaction between tumor necrosis factor-alpha (TNF) production and the alpha(2)-adrenergic receptor response, offering an attractive therapeutic target. The effects of varying levels of brain TNF on alpha(2)-adrenergic regulation of cyclic AMP (cAMP) production in the hippocampus and sciatic nerve were investigated during the development and amitriptyline treatment of chronic pain. Increased levels of TNF during the development of chronic pain transform alpha(2)-adrenergic inhibition of cAMP production in the brain to potentiation. While alpha(2)-adrenergic receptors regulate TNF production, they also affect descending noradrenergic pathways. Increases in levels of TNF in the brain deeply impact peripheral inflammation through regulating alpha(2)-adrenergic receptors, offering insight into brain-body interactions during neuropathic pain. Amitriptyline as an analgesic inhibits pain-induced increases in brain-associated TNF and transforms peripheral alpha(2)-adrenergic receptors. The dynamic equilibrium between TNF levels and alpha(2)-adrenergic functioning is uniquely altered during development and treatment of neuropathic pain. Proper manipulations of this interaction offer efficacious treatment of neuropathic pain.
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PMID:Uncovering molecular elements of brain-body communication during development and treatment of neuropathic pain. 1685 92

Developmentally, semaphorin 3A (sema3A) is an important chemorepellent that guides centrally projecting axons of dorsal root ganglion (DRG) neurons. Sema3A-mediated growth cone collapse can be prevented by cyclic GMP (cGMP) and nerve growth factor (NGF) in embryonic neurons. Sema3A may also play a role in directing regrowth of injured axons in adults, and interactions with neurotrophic factors near the injury site may determine the extent and targeting of both regenerative and aberrant growth. The aim of this study was to determine whether NGF, glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) modulate sema3A-mediated growth cone collapse in cultured adult rat DRG neurons. Sema3A caused a significant increase in growth cone collapse, which was completely prevented by prior treatment with NGF, GDNF or NTN. Immunocytochemical experiments showed that sema3A-sensitive neurons were heterogeneous in their expression of neurotrophic factor receptors and responses to neurotrophic factors, raising the possibility of novel, convergent signaling mechanisms between these substances. Increasing cGMP levels caused growth cone collapse, whereas sema3A-mediated collapse was prevented by inhibition of guanylate cyclase or by increasing cyclic AMP levels. In conclusion, sema3A signaling pathways in adult neurons differ to those described in embryonic neurons. Three different neurotrophic factors each completely prevent sema3A-mediated collapse, raising the possibility of novel converging signaling pathways. These studies also show that there is considerable potential for neurotrophic factors to regulate sema3A actions in the adult nervous system. This may provide insights into the mechanisms underling misdirected growth and targeting of sensory fibers within the spinal cord after injury, that is thought to contribute to development of autonomic dysreflexia and neuropathic pain.
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PMID:Nerve growth factor, glial cell line-derived neurotrophic factor and neurturin prevent semaphorin 3A-mediated growth cone collapse in adult sensory neurons. 1687 31

Visceral noxious stimulation induces central neuronal plasticity changes and suggests that the c-AMP-dependent protein kinase (PKA) signal transduction cascade contributes to long-term changes in nociceptive processing at the spinal cord level. Our previous studies reported the clinical neurosurgical interruption of post synaptic dorsal column neuron (PSDC) pathway by performing midline myelotomy effectively alleviating the intractable visceral pain in patients with severe pain. However, the intracellular cascade in PSDC neurons mediated by PKA nociceptive neurotransmission was not known. In this study, by using multiple experimental approaches, we investigated the role of PKA in nociceptive signaling in the spinal cord and PSDC neurons in a visceral pain model in rats with the intracolonic injection of mustard oil. We found that mustard oil injection elicited visceral pain that significantly changed exploratory behavior activity in rats in terms of decreased numbers of entries, traveled distance, active and rearing time, rearing activity and increased resting time when compared to that of rats receiving mineral oil injection. However, the intrathecal infusion of PKA inhibitor, H89 partially reversed the visceral pain-induced effects. Results from Western blot studies showed that mustard oil injection significantly induced the expression of PKA protein in the lumbosacral spinal cord. Immunofluorescent staining in pre-labeled PSDC neurons showed that mustard oil injection greatly induces the neuronal profile numbers. We also found that the intrathecal infusion of a PKA inhibitor, H89 significantly blocked the visceral pain-induced phosphorylation of c-AMP-responsive element binding (CREB) protein in spinal cord in rats. The results of our study suggest that the PKA signal transduction cascade may contribute to visceral nociceptive changes in spinal PSDC pathways.
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PMID:The role of c-AMP-dependent protein kinase in spinal cord and post synaptic dorsal column neurons in a rat model of visceral pain. 1732 Feb 44

Chronic inflammatory and neuropathic pain is often difficult to manage using conventional remedies. The underlying mechanisms and therapeutic strategies required for the management of chronic pain need to be urgently established. The cyclic AMP (cAMP) second messenger system has been implicated in the mechanism of nociception, and the inhibition of the cAMP pathway by blocking the activities of adenylyl cyclase (AC) and protein kinase A has been found to prevent chronic pain in animal models. However, little is known regarding which of the 10 known isoforms of AC are involved in nociceptive pathways. Therefore, we investigated the potential pronociceptive function of AC5 in nociception using recently developed AC5 knockout mice (AC5-/-). We found that AC5-/- mice show markedly attenuated pain-like responses in acute thermal and mechanical pain tests as compared with the wildtype control. Also, AC5-/- mice display hypoalgesic responses to inflammatory pain induced by subcutaneous formalin injection into hindpaws, and to non-inflammatory and inflammatory visceral pain induced by injecting magnesium sulfate or acetic acid into the abdomen. Moreover, AC5-/- mice show strongly suppressed mechanical and thermal allodynia in two nerve injury-induced neuropathic pain models. These results suggest that AC5 is essential for acute and chronic pain, and that AC5 knockout mice provide a useful model for the evaluation of the pathophysiological mechanisms of pain.
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PMID:Markedly attenuated acute and chronic pain responses in mice lacking adenylyl cyclase-5. 1741 Jun 41

In our aging population, primary major amputations (AMP, below-knee or above-knee) continue to be performed despite advances in revascularization. We hypothesized that not only patient comorbidities but also the system of health-care delivery affected the treatment of patients with critical limb ischemia (CLI). A prospective analysis of patients presenting with CLI was undertaken to determine whether patient-specific factors or healthcare delivery factors (system-related) influenced treatment with primary AMP versus lower extremity revascularization (LER). The patient-specific factors age, gender, race/ethnicity, presence of coronary artery disease, cerebrovascular disease, tobacco use, diabetes mellitus (DM), dialysis dependence (end-stage renal disease, ESRD), hypertension, hyperlipidemia, stage of CLI (rest pain, minor or major tissue loss), history of revascularization, and functional status (living situation and ambulatory status) were recorded. The system-related factors time from onset of CLI to vascular surgery evaluation and type of insurance (managed care/other insurance) were also noted. The influence of patient-specific and system-related factors on the primary treatment modality (AMP versus LER) was determined with univariate and multivariate analyses. A total of 224 patients presented with CLI between March 1, 2001, and March 1, 2005. Patients were treated with primary major AMP in 97 cases (43%) and revascularization in 127 cases (57%). On univariate analysis, nonwhite race/ethnicity, DM, ESRD, major tissue loss, dependent living situation, and nonambulatory status were all significant predictors of AMP versus LER (all P < 0.01). On multivariate analysis, major tissue loss, ESRD, DM, and nonambulatory status remained independent predictors of AMP versus LER (all P < 0.05). The system-related factors of time to vascular surgery evaluation (mean 8.6 weeks, 7.1 vs. 9.3 weeks AMP versus LER, P = 0.60) and type of insurance (managed care, 17% vs. 24% AMP vs. LER, P = 0.15) had no influence on treatment. Fifty-four percent of all primary major AMPs were performed due to extensive gangrene or infection present at initial vascular evaluation which precluded limb salvage. Major tissue loss, ESRD, DM, and nonambulatory status are all independent predictors of treatment with primary AMP as opposed to revascularization. Treatment of CLI is determined by patient-specific factors and does not appear to be adversely influenced by system-related factors. Efforts toward improving limb salvage may be best directed at aggressive treatment of medical comorbidities to prevent the late complications of CLI. Earlier recognition of tissue loss and referral to the vascular specialist may lead to improved limb salvage.
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PMID:A prospective analysis of critical limb ischemia: factors leading to major primary amputation versus revascularization. 1749 67


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