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

Increased synthesis of substance P (SP) in the dorsal root ganglia (DRG) and enhanced axonal transport to and secretion from the primary afferent sensory neurons might enhance pain signalling in the spinal dorsal horn by modifying pronociceptive pathways. IL-1beta increases SP synthesis by enhancing the expression of preprotachykinin (PPT) mRNA encoding for SP and other tachykinins in the DRG. Stimulation of IL-1 receptor by IL-1beta may induce the phosphorylation of tyrosine residues in many effector proteins through the activation of p60c-src kinase. The hypothesis that the synthesis of SP in and secretion from the primary sensory ganglia are regulated by the activation of p60c-src kinase induced by IL-1beta was tested. Pretreatment of DRG neurons in culture with herbimycin A, genistein or PP2, three structurally different nonreceptor tyrosine kinase inhibitors that act by different mechanisms, decreased the kinase activity of p60c-src induced by the activation of IL-1 receptor. PP3, a negative control for the Src family of tyrosine kinase inhibitor PP2 had no effect. Herbimycin A and genistein also decreased IL-1beta-induced expression of PPT mRNA-encoding transcripts and the levels of SP-li synthesized in the cells and secreted into the culture medium in a concentration-dependent manner. SB 203580 [a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor] and PD 98059 (a p44/42 MAPK kinase inhibitor) were ineffective in modulating IL-1beta-induced SP synthesis and secretion, and p60c-src kinase activity in DRG neurons. Whereas, IL-1 receptor antagonist and cycloheximide inhibited IL-1beta-evoked secretion of SP-like immunoreactivity (SP-li), actinomycin D decreased it significantly but did not entirely abolish it. These findings show that phosphorylation of specific protein tyrosine residue(s) following IL-1 receptor activation might play a key role in IL-1beta signalling to modulate PPT gene expression and SP secretion in sensory neurons. In view of the role of SP as an immunomodulator, these studies provide a new insight into neural-immune intercommunication in pain regulation in the sensory ganglia through the IL-1beta-induced p60c-src activation.
 ...
PMID:c-Src kinase activation regulates preprotachykinin gene expression and substance P secretion in rat sensory ganglia. 1462 6

Ideally, treatment is based on etiology, if possible on pathophysiology, and in practice on anatomical and clinical findings. A systematic search for the etiological factors of osteoarthritis (OA) shows that the various mechanisms are frequently associated. Etiological treatments are rare. We may mention acetabular tectoplasty in hip dysplasia with minimal joint space narrowing. Valgus osteotomy would also be indicated for early medial tibiofemoral OA in genu varum if we had definite proof that, if left untreated, this deformity inevitably leads to clinically severe OA. This is not the case. One of the limitations of this etiological treatment lies in the fact that we do not know which patients are at risk of developing painful OA. Instead, certain risk factors for OA are known, so that primary and secondary prevention of the disease is possible. While age, sex and genetic predisposition are not amenable to preventive action, the same does not apply to the following factors: obesity, sports, and occupational activity. Thanks to in vitro studies of cultured normal and osteoarthritic chondrocytes and to experimental models of OA in animals, the pathophysiological mechanisms of OA are beginning to be better known. The prospect thus arises of "therapeutic manipulations" of precise pharmacological targets, even if it is still too soon to speak of true pathophysiological treatment of this disease. For instance, various interventions along the IL-1 pathway can be envisaged and have all been tested in animals. In practice, treating OA means taking into consideration its various signs: pain which appears to be mechanical and more or less chronic, joint stiffness, instability, effusion, and--the consequence of these symptoms--the professional, social and personal handicap of the patient. The treatment of OA must be approached from a global perspective, associating whenever possible symptomatic treatment, disease-modifying treatment, education and rehabilitation. In other words, the treatment of OA requires an overall approach, associating pharmacological and non-pharmacological modalities.
 ...
PMID:The therapeutic approach to osteoarthritis. 1470 6

Based on a hypothesis that interleukin 1 (IL-1) activity is associated with low back pain (LBP), we investigated relationships between previously described functional IL-1 gene polymorphisms and LBP. The subjects were a subgroup of a Finnish study cohort. The IL-1alpha(C(889)-T), IL-1beta(C(3954)-T) and IL-1 receptor antagonist (IL-1RN)(G(1812)-A, G(1887)-C and T(11100)-C) polymorphisms were genotyped in 131 middle-aged men from three occupational groups (machine drivers, carpenters and office workers). A questionnaire inquired about individual and lifestyle characteristics and the occurrence of LBP, the number of days with pain and days with limitation of daily activities because of pain, and pain intensity, during the past 12 months. Lumbar disc degeneration was determined with magnetic resonance imaging. Carriers of the IL-1RNA(1812) allele had an increased risk of LBP (OR 2.5, 95% CI 1.0-6.0) and carriers of this allele in combination with the IL-1alphaT(889) or IL-1betaT(3954) allele had a higher risk of and more days with LBP than non-carriers. Pain intensity was associated with the simultaneous carriage of the IL-1alphaT(889) and IL-1RNA(1812) alleles (OR 3.7, 95% CI 1.2-11.9). Multiple regression analyses allowing for occupation and disc degeneration showed that carriage of the IL-1RNA(1812) allele was associated with the occurrence of pain, the number of days with pain and days with limitations of daily activities. Carriage of the IL-1betaT(3954) allele was associated with the number of days with pain. The results suggest a possible contribution of the IL-1 gene locus polymorphisms to the pathogenesis of LBP. The possibility of chance findings cannot be excluded due to the small sample size.
Pain 2004 May
PMID:Possible association of interleukin 1 gene locus polymorphisms with low back pain. 1508 21

The brain-derived interleukin-1beta (IL-1beta) has been involved in the modulation of nociceptive processing. The direction of the effects, however, analgesia or hyperalgesia, is controversial. Here, we report the role of IL-1beta injected intracisternally in orofacial pain transmission. Experiments were carried out on 90 male SD rats and surgical procedures were performed under pentobarbital sodium. Intracisternal injection of 0.3 or 0.6 microg of N-methyl-d-aspartic acid (NMDA) produced intense scratching behavioral responses including vocalization, agitation and a desire to escape in a dose-related manner. The intracisternal injection of 1 or 10 ng IL-1beta significantly decreased the NMDA-evoked scratching behavioral responses. Pretreatment with an IL-1 receptor antagonist or naloxone, an opioid receptor antagonist, blocked the IL-1beta-induced antinociceptive response. These results suggest that cytokine injected intracisternally seems to produce antinociceptive effects in the NMDA-evoked pain model of the orofacial area and the antinociceptive effect seems to be mediated by an opioid pathway.
 ...
PMID:Interleukin-1 beta injected intracisternally inhibited NMDA-evoked behavioral response in the orofacial area of freely moving rats. 1508 73

Anakinra (Amgen, Inc.) is a specific receptor antagonist of IL-1 that differs from naturally occurring IL-1 receptor antagonist by the presence of a methionine group. Anakinra has been shown to be of benefit in patients with active rheumatoid arthritis, either when given alone or in combination with methotrexate, as assessed by improvement in clinical signs and symptoms, decreased radiographic progression and improvement in patient function, pain and fatigue, although it appears to be effective in fewer patients than anti-TNF agents. It has a favourable safety profile as demonstrated in clinical trials. The physician and patient must be cognizant of serious infectious episodes. Many of the rare side effects seen with TNF blockers, such as tuberculosis, other opportunistic infections, worsening of congestive heart failure and the development of demyelinating disease, have not been seen in patients treated with anakinra. Anakinra should not be given in combination with anti-TNF agents.
 ...
PMID:Anakinra: an inhibitor of IL-1 for the treatment of rheumatoid arthritis. 1526 66

The postoperative period is associated with an increased production of cytokines, which augment pain sensitivity. We investigated the hypothesis that epidural clonidine premedication and postoperative patient-controlled epidural analgesia (PCEA) including clonidine would decrease the release of proinflammatory (interleukin (IL)-6, IL-1beta, IL-8, and tumor necrosis factor (TNF)-alpha) and antiinflammatory (IL-1 receptor antagonist (RA)) cytokines in patients who underwent elective colorectal surgery and that they would provide better postoperative analgesia. Forty patients were randomly assigned to 1 of 2 groups of 20 each: the control group received normal saline 10 mL, whereas the clonidine group received epidural clonidine 150 microg diluted with 9 mL of normal saline 30 min before surgery. Venous blood samples for cytokine levels were obtained before induction, at the end of surgery, and after surgery at 12 and 24 h. After surgery, the clonidine group patients received PCEA with morphine (0.1 mg/mL) and clonidine (1.5 microg/mL) in 0.2% ropivacaine 100 mL, whereas control group patients received only PCEA morphine and ropivacaine. Patients in the clonidine group exhibited longer PCEA trigger times, lower pain scores at rest and while coughing, less morphine consumption, and a faster return of bowel function throughout the 72-h postoperative observation period, compared with patients in the control group. For patients in the clonidine group, production of IL-1RA, IL-6, and IL-8 was significantly less increased at the end of the surgical procedure and at 12 and 24 h after surgery. However, the concentrations of IL-1beta and TNF-alpha were not significantly increased.
 ...
PMID:The effect of epidural clonidine on perioperative cytokine response, postoperative pain, and bowel function in patients undergoing colorectal surgery. 1527 31

Cytokine release during surgery can produce a long-lasting hyperalgesia. Thus, preoperatively-administered cytokine inhibitors might reduce the production of cytokines, decreasing central nervous system sensitization and improving the quality of postoperative pain relief. We investigated the hypothesis that preincisional IV pentoxifylline (PTX) treatment could attenuate the release of proinflammatory (tumor necrosis factor, interleukin (IL)-1beta, IL-6, and IL-8) and antiinflammatory (IL-1 receptor antagonist) cytokines in patients who underwent elective colorectal cancer surgery. Forty patients were randomly assigned to 1 of 2 groups of 20 each: the PTX group received a PTX 5 mg/kg IV infusion before the induction of anesthesia, whereas the control group received an equal volume of normal saline. Venous blood samples were obtained at frequent intervals. After surgery, all patients received patient-controlled analgesia (PCA) morphine for postoperative pain relief. Patients in the PTX group exhibited longer PCA trigger times, less morphine consumption, and a faster return of bowel function compared with patients in the control group. Moreover, the plasma levels of IL-6, IL-8, and IL-1 receptor antagonist were less in the treatment group, and there was no significant difference in wound infections, tumor recurrence, or metastatic rates between groups during a 2-yr follow-up.
 ...
PMID:Preincisional intravenous pentoxifylline attenuating perioperative cytokine response, reducing morphine consumption, and improving recovery of bowel function in patients undergoing colorectal cancer surgery. 1550 50

Tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) are pro-inflammatory cytokines capable of altering the sensitivity of sensory neurons. Because sensitization elicited by IL-1beta and TNFalpha is blocked by inhibition of the inducible enzyme, cyclooxygenase-II (COX-2), we examined whether these cytokines could increase COX-2 expression in dorsal root ganglion (DRG) cultures. Treatment of cell cultures with either IL-1beta or TNFalpha increases immunoreactive COX-2, as measured by immunoblotting, in a time- and concentration-dependent manner. A 24-h pretreatment with 10 ng/ml IL-1beta or 50 ng/ml TNFalpha augmented COX-2 expression 50- and 8-fold over basal levels, respectively. Immunohistochemistry established the presence of COX-2-like immunoreactivity in both neuronal and non-neuronal cells in culture. The addition of IL-1 receptor antagonist blocked the induction of COX-2 expression by IL-1beta, but did not alter TNFalpha-stimulated increases in COX-2, indicating that the mechanism of TNFalpha is not limited to increasing the expression of IL-1beta. The basal and TNFalpha-induced expression of COX-2 was not dependent on the presence of NGF in the growth media. IL-1beta and TNFalpha treatment for 24 h enhanced prostaglandin E2 (PGE2) production 2-4-fold, which was blocked by pretreatment with the COX-2 inhibitor, NS-398. Exposing cultures to PGE2, IL-1beta, or TNFalpha for 24 h did not alter PGE2 receptor (EP) mRNA levels. These results indicate that TNFalpha and IL-1beta induce the functional expression of COX-2 but not EP receptors in DRG cells in culture and suggest that cytokine-induced sensitization of sensory neurons is secondary to prostaglandin production and not alterations in EP receptors.
Pain 2005 Jan
PMID:Tumor necrosis factor alpha and interleukin-1beta stimulate the expression of cyclooxygenase II but do not alter prostaglandin E2 receptor mRNA levels in cultured dorsal root ganglia cells. 1562 71

Rheumatoid arthritis (RA) is a chronic progressive disease of the joints associated with significant morbidity, deformity, and impaired quality of life. A satisfactory remission of disease is seldom achieved, so therapy is aimed at controlling joint damage and pain with preservation of joint mobility. Until recently, NSAIDs, followed by DMARDs, was considered the treatment of choice. However, many patients fail to gain a satisfactory response to DMARDs or response declines over time. Biologics such as IL-1 receptor antagonist (anakinra), and anti TNF-alpha agents (Etanercept, Infliximab, and Adalimumab) are now available. The anti TNF and IL-1 therapies exert their anti-inflammatory action by neutralizing the activities of TNF-alpha and IL-1 respectively. In contrast to older DMARDs, these agents have rapid onset of action with fewer side effects and have pronounced disease reducing activity in patients who have previously been treated with other DMARDs, when administered as monotherapy or in combination with methotrexate. They have been shown to be at least as effective as methotrexate in reducing clinical disease activity and reducing radiographic progression. Biological agents are generally well tolerated, although their long-term safety needs to be determined. Some concerns have been raised that anti TNF-alpha therapy can increase the risk of serious infections, since TNF-alpha plays an important role in host defense. In light of limitations of cost and lack of long-term safety and efficacy data, newer agents for the time being are used as second- or third-line agents in patients with active RA. The dilemma is that which patients with RA are most suitable for such therapy, since it is still not possible to accurately predict which patient with RA will develop severe disease. One alternative approach may be to limit the use in patients who can afford it, and who are at high risk of radiographic progression and disability.
 ...
PMID:Biologics in rheumatoid arthritis. 1563 15

Activated glial cells (microglia and astroglia) in the spinal cord play a major role in mediating enhanced pain states by releasing proinflammatory cytokines and other substances thought to facilitate pain transmission. In the present study, we report that intrathecal administration of minocycline, a selective inhibitor of microglial cell activation, inhibits low threshold mechanical allodynia, as measured by the von Frey test, in two models of pain facilitation. In a rat model of neuropathic pain induced by sciatic nerve inflammation (sciatic inflammatory neuropathy, SIN), minocycline delayed the induction of allodynia in both acute and persistent paradigms. Moreover, minocycline was able to attenuate established SIN-induced allodynia 1 day, but not 1 week later, suggesting a limited role of microglial activation in more perseverative pain states. Our data are consistent with a crucial role for microglial cells in initiating, rather than maintaining, enhanced pain responses. In a model of spinal immune activation by intrathecal HIV-1 gp120, we show that the anti-allodynic effects of minocycline are associated with decreased microglial activation, attenuated mRNA expression of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-1beta-converting enzyme, TNF-alpha-converting enzyme, IL-1 receptor antagonist and IL-10 in lumbar dorsal spinal cord, and reduced IL-1beta and TNF-alpha levels in the CSF. In contrast, no significant effects of minocycline were observed on gp120-induced IL-6 and cyclooxygenase-2 expression in spinal cord or CSF IL-6 levels. Taken together these data highlight the importance of microglial activation in the development of exaggerated pain states.
Pain 2005 May
PMID:Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. 1583 71


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>