Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This short review updates information on the release mechanisms of the systemic response to surgical injury and the modifying effect of pain relief. Initiation of the response is primarily due to afferent nerve impulses combined with release of humoral substances (such as prostaglandins, kinins, leukotrienes, interleukin-1, and tumor necrosis factor), while amplification factors include semi-starvation, infection, and hemorrhage. The relative role of the various signals in producing the complex injury response has not been finally determined, but the neural pathway is probably most important in releasing the classical endocrine catabolic response, while humoral factors are important for the hyperthermic response, changes in coagulation and fibrinolysis immunofunction, and capillary permeability. The modifying effect of pain relief on the surgical stress response is dependent upon the technique of analgesia. However, the effect on humoral-mediated responses is small, regardless of the technique used. Afferent neural blockade with local anesthetics is the most effective technique for reducing the endocrine-metabolic response, but only in operations in the lower part of the abdomen, probably because of insufficient afferent blockade during thoracic epidural analgesia. Systemic opiate administration, as well as non-steroidal antiinflammatory drugs, exert only a small modifying effect on the response. Low-dose combined analgesic regimens may provide total pain relief, but exert no important effect on the stress response. In summary, pain alleviation itself may not necessarily lead to an important modification of the stress response, and a combined approach with inhibition of the neural and humoral release mechanisms is necessary for a pronounced inhibition or prevention of the response to surgical injury.
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PMID:The stress response to surgery: release mechanisms and the modifying effect of pain relief. 265 70

Fentanyl citrate analgesia attenuates the excess nitrogen excretion in the urine and glucose production induced by trauma. On the other hand, intracerebroventricular injection of morphine stimulates excretion of stress hormones, such as catecholamines and corticosterone. Furthermore, morphine levels in the brain are increased during fasting and sepsis. The aims of this study were to determine whether intracerebroventricular injection of tumor necrosis factor-alpha (TNF-alpha) elevates morphine levels in the rat brain and whether prophylactic administration of fentanyl blocks metabolic responses induced by intracerebroventricular injection of TNF-alpha because of a reduction of morphine levels in the brain. Morphine levels in the brain were increased from 648 to 1,134 fmol/g at 30 min after intracerebroventricular injection of TNF-alpha (P < 0.05 vs. control). This increase was associated with an increase in stress hormones (corticosterone: 416.1 +/- 69.1 ng/ml, P < 0.05 vs. control; epinephrine: 3,778.3 +/- 681.3 pg/ml, P < 0.01 vs. control) and an enhancement of proteolysis (254.2 +/- 45.7 micromol Leu . kg-1 . h-1, P < 0.01 vs. control) and glucose production (7.5 +/- 0. 7 mg . kg-1 . min-1, P < 0.05 vs. control). Fentanyl reduced morphine levels in the brain to 624 fmol/g (not significant vs. control), resulting in a reduction of stress hormone levels in the plasma and blunted metabolic responses. In conclusion, prophylactic administration of fentanyl prevented an increase in morphine levels in the brain induced by intracerebroventricular injection of TNF-alpha, leading to a reduction in stress hormone levels and subsequent metabolic responses.
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PMID:Effect of fentanyl on morphine levels in the brain in rats receiving intracerebroventricular injection of TNF-alpha. 975 82

Among nonsteroidal anti-inflammatory drugs (NSAIDs), 2-arylpropionic acids exist as a racemic mixture of its enantiomeric forms, with S-enantiomers primarily responsible for inhibition of prostaglandin synthesis and of inflammatory events. The aim of this study was to compare the anti-inflammatory effects of R- and S-ketoprofen in vitro and in vivo. S-Ketoprofen efficiently inhibited carrageenan-induced edema formation, but it could also amplify the LPS-induced production of the inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1), in close correlation with its ability to inhibit prostaglandin synthesis. Because these inflammatory cytokines are among the factors involved in carrageenan-induced inflammation and also are possibly involved in gastric damage, enhanced cytokine production could partially mask the analgesic effect of S-ketoprofen, and it can be associated with the clinical evidence of its gastric toxicity. On the other hand, R-ketoprofen contributes to the overall activity of the racemate, by playing the main role in ketoprofen-induced analgesia. Unlike the S-isomer, R-ketoprofen did not induce a significant increase of cytokine production even at cyclooxygenase-blocking concentrations. It is concluded that the R-isomer directly contributes to the anti-inflammatory effects of ketoprofen, being more analgesic, and because it does not amplify inflammatory cytokine production.
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PMID:Differential contribution of R and S isomers in ketoprofen anti-inflammatory activity: role of cytokine modulation. 986 81

Possible contributions of the hypothalamo-hypophyseal-adrenal axis to the development of adjuvant-induced arthritis and therapeutic actions of the prototypical kappa-opioid agonist PNU-50,488H (PNU-50) were studied in DA rats. Paw edema, nociception, histological and radiological joint damage, and tumor necrosis factor-alpha release by peritoneal macrophages were measured in adrenalectomized (ADX) and sham-operated (SHO) arthritic animals (drug-treated and untreated groups). Disease developed earlier in ADX rats (paw edema was first apparent 11 days postadjuvant compared with day 13 in SHO animals) and remained more severe in that group. Twice-daily PNU-50 treatment completely prevented the development of edema in the SHO group but was effective in the ADX animals only on day 18. PNU-50 substantially reduced the pooled severity index (combined quantitative edema, histological and radiological assessments) at day 18 in both SHO and ADX rats and to an equal extent. During disease development, the paws of SHO, but not ADX, rats became hyperalgesic; paradoxically, ADX animals were hyperalgesic during PNU-50 treatment, but the drug produced analgesia in SHO animals. Compared with cells harvested from healthy animals, macrophages from arthritic rats released about twice as much tumor necrosis factor-alpha after lipopolysaccharide stimulation. It was concluded that the hypothalamo-hypophyseal-adrenal axis influences the development of adjuvant arthritis and plays a partial role in the therapeutic action of the kappa-agonist PNU-50.
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PMID:The importance of the hypothalamo-hypophyseal-adrenal axis to the anti-inflammatory actions of the kappa-opioid agonist PNU-50,488H in rats with adjuvant arthritis. 1094 69

Opioids and their receptors are key players in a cross-talk between the nervous and immune systems. For example, the endogenous opioid system is activated during inflammation as a physiological feedback mechanism to attenuate inflammatory pain. Herein, we report that in primary human T lymphocytes, Raji B cells, U937 monocytes, primary human polymorphonuclear leukocytes, and mature dendritic cells, the proinflammatory cytokine tumor necrosis factor induced mu-opioid receptor gene transcription. Transcriptional induction of the gene in immune cells was mediated via tumor necrosis factor receptor type 2. Using selective in vivo disruption of possibly involved transcription factors with decoy oligonucleotides, nuclear factor-kappaB was identified as the factor responsible for induction of the gene in immune cells, whereas activator protein-1 was found to be uninvolved. Nuclear factor-kappaB also mediates up-regulation of mu-opioid receptors in neuronal cells stimulated with tumor necrosis factor. Among six putative nuclear factor-kappaB binding sites on the mu-opioid receptor gene promoter, three cis-active elements at nt -2174, -557, and -207 were identified using transfection experiments of reporter gene constructs, electrophoretic mobility shift assays, and in vivo binding studies with decoy oligonucleotides. An allelic variation within the -557 element significantly reduced its trans-activating potency, which may affect regulation of the mu-opioid receptor gene in persons carrying this mutation. This study suggests a regulatory function of tumor necrosis factor in opioid-mediated processes in neuronal and immune cells, with possible impact on the complex of inflammation-induced analgesia.
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PMID:The role of nuclear factor kappaB in tumor necrosis factor-regulated transcription of the human mu-opioid receptor gene. 1450 Jul 35

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.
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PMID:The effect of epidural clonidine on perioperative cytokine response, postoperative pain, and bowel function in patients undergoing colorectal surgery. 1527 31

During inflammatory processes, the hypothalamic-pituitary axis is activated which can subsequently result in analgesia. For example, hypothalamic corticotrophin-releasing hormone (CRH) that is released during such activation has been attributed with analgesic actions. It is believed that the somatotrophic axis is also activated during inflammation. The aim of this study was to determine the analgesic actions of growth hormone-releasing hormone (GHRH), in a rat model of localized inflammatory hyperalgesia, induced by intraplantar (i.pl.) endotoxin (ET) injections. Pretreatment with intraperitoneal (i.p.) injections of GHRH (2, 5, 10 microg kg(-1)) 30 min before i.pl. ET injection (1.25 microg in 50 microl saline) prevented, in a dose-dependent manner, both mechanical hyperalgesia determined by the paw pressure (PP) test and thermal hyperalgesia determined by the hot plate (HP) and paw immersion (PI) tests. Pretreatment with GHRH had no significant effect on the elevated levels of the inflammatory mediators, interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, IL-6 and nerve growth factor (NGF) due to i.pl. ET injection. No significant effect was obtained by pretreatment with GHRH, on the increased expression of gelatinase B due to ET injection. In conclusion, GHRH reverses inflammatory hyperalgesia in the rat without affecting the upregulated inflammatory mediators and these actions may be clinically important.
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PMID:Growth hormone releasing hormone reverses endotoxin-induced localized inflammatory hyperalgesia without reducing the upregulated cytokines, nerve growth factor and gelatinase activity. 1527 87

We tested the hypothesis that the ability of granulocyte colony-stimulating factor (G-CSF) to prevent death from fecal peritonitis is influenced by the composition of the antibiotic regimen with which it is administered. We used a rodent model of polymicrobial peritoneal contamination and infection and the concept of clinical modeling randomized trials (CMRTs), which includes the conditions of randomized, clinical trials and complex clinical interventions (e.g., anesthesia, volume substitution, antibiotics, surgery, postoperative analgesia). With the peritonitis model we obtained a mortality dose-response curve that was sensitive to antibiotic prophylaxis. G-CSF was most efficacious when it was administered both prophylactically and after the onset of peritonitis. Cefuroxime/metronidazole, ofloxacin/metronidazole, and amoxicillin/clavulanate improved survival in combination with G-CSF best, whereas cefotaxime or ceftriaxone with and without metronidazole did not. G-CSF administration was associated with improved polymorphonuclear neutrophil phagocytosis and enhanced bacterial clearance. Pro-inflammatory cytokine release (tumor necrosis factor-a, interleukin-6, macrophage inflammatory protein-2) was decreased in plasma and in the peritoneal fluid. Their expression was lowered in various organs on the protein and mRNA level. The results were used to design a clinical trial to test the ability of G-CSF to prevent serious infections in patients with colorectal cancer surgery. In this trial G-CSF application and antibiotic prophylaxis were performed with the most effective scheduling and combinations (cefuroxime/metronidazole and ofloxacin/metronidazole) as defined here.
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PMID:Dependence of positive effects of granulocyte colony-stimulating factor on the antibiotic regimen: evaluation in rats with polymicrobial peritonitis. 1545 67

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.
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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

Despite the widespread use of radiotherapy to treat painful bone metastases, the mechanism underlying the analgesic effect of low dose ionizing radiation is unknown. Bone cancer pain is mostly associated with an inflammatory response dominated by local activation of osteoclasts and by astrogliosis in the spinal cord. We determined the effects of a 6 Gy irradiation given focally on osteolytic sarcoma cells inoculated in humeri of mice. Pain behavior was assessed using the rota-rod and the grip force test. Seven days post-irradiation (day 17 post-tumor implantation) the performance of mice markedly improved on the rotarod (non-irradiated, 67+/-16s vs irradiated, 223 +/- 22 s; P = 0.0005), and the grip force test (non-irradiated, 34 +/- 4 g vs irradiated, 55 +/- 2 g; P = 0.001). This improvement was similar to the analgesia achieved with 30 mg/kg of the cyclooxygenase (COX) inhibitor ketorolac (Rota-rod, 67 +/- 16 s vs 178 +/- 35 s; P = 0.01: grip force test, 34 +/- 4 g, vs 60 +/- 5 g; P = 0.003). Following irradiation, the tumor mass and the number of osteoclasts did not decrease while the expression of two pro-inflammatory cytokines (monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha) increased. Tumor irradiation led to clear differences in the spinal cord. These include a decrease in glial activity (astrocytes and microglial cells) as well as pain mediators such as dynorphin, COX-2 and chemotactic cytokine receptor (CCR2). We conclude that the analgesic effect of low dose irradiation of bone cancer is associated with the alteration of nociceptive transmission in the central nervous system.
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PMID:The analgesic effect of low dose focal irradiation in a mouse model of bone cancer is associated with spinal changes in neuro-mediators of nociception. 1636 Feb 79


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