Selective attention for pain-related information in healthy individuals: the role of pain and fear.

The aim of this study was to investigate whether pain itself or pain-related fear is crucial in eliciting attentional bias towards pain-related information in healthy individuals. The results from two successive experiments provide evidence that attentional bias does not take place as a function of pain-related fear or as a function of pain per se. Attentional bias for pain words was neither found to be related to trait variables like anxiety, depression, catastrophising, fear of pain, and pain vigilance. Implications of the results are discussed and directions for future research are provided.     

Selective regulation of cellular cyclooxygenase by dexamethasone and endotoxin in mice.

We have studied the effect of glucocorticoids administered in vivo on the activity and synthesis of the cyclooxygenase enzyme (COX) in mice treated with or without concurrent intravenous administration of LPS. Mouse peritoneal macrophages from LPS-treated animals showed a two to three fold increase in COX activity determined by the production of PGE2 and PGI2 after stimulation of the cells with exogenous arachidonate. Dexamethasone injected simultaneously with LPS, 12 h before killing of the animal and removal of the macrophages, completely blocked the LPS-induced increase COX activity in peritoneal macrophages. The regulation observed in COX activity by LPS and dexamethasone are due primarily to changes in COX mass as determined by immunoprecipitation of [35S]methionine endogenously labeled enzyme. In contrast, the COX present in the nonadherent cells and in renal medullary microsomes obtained from the same animals, showed no significant changes between treatments. These results indicate that LPS in vivo stimulates COX synthesis in the peritoneal macrophages but not in the kidney. The effect of dexamethasone to inhibit COX synthesis is selective to the LPS-induced enzyme.     

Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis.

Prostaglandins formed by the cyclooxygenase (COX) enzymes are important mediators of inflammation in arthritis. The contribution of the inducible COX-2 enzyme to inflammation in rat adjuvant arthritis was evaluated by characterization of COX-2 expression in normal and arthritic paws and by pharmacological inhibition of COX-2 activity. The injection of adjuvant induced a marked edema of the hind footpads with coincident local production of PGE2. PG production was associated with upregulation of COX-2 mRNA and protein in the affected paws. In contrast, the level of COX-1 mRNA was unaffected by adjuvant injection. TNF-alpha and IL-6 mRNAs were also increased in the inflamed paws as was IL-6 protein in the serum. Therapeutic administration of a selective COX-2 inhibitor, SC-58125, rapidly reversed paw edema and reduced the level of PGE2 in paw tissue to baseline. Interestingly, treatment with the COX-2 inhibitor also reduced the expression of COX-2 mRNA and protein in the paw. Serum IL-6 and paw IL-6 mRNA levels were also reduced to near normal levels by SC-58125. Furthermore, inhibition of COX-2 resulted in a reduction of the inflammatory cell infiltrate and decreased inflammation of the synovium. Notably, the antiinflammatory effects of SC-58125 were indistinguishable from the effects observed for indomethacin. These results suggest that COX-2 plays a prominent role in the inflammation associated with adjuvant arthritis and that COX-2 derived PGs upregulate COX-2 and IL-6 expression at inflammatory sites.     

Current concepts in cyclooxygenase inhibition in breast cancer

The prospect that simple medications such as non-steroidal anti-inflammatory drugs (NSAIDs) could be recruited into the physician's armamentarium of anticancer drugs is intriguing, especially in the context of breast cancer, one of the leading causes of mortality in the Western world. There has consequently been a wider exploration of the role of cyclooxygenase (COX) in breast cancer, and we now accept that COX-2, one of its isoenzymes, is clearly implicated in the pathogenesis of the disease. This would seem to translate into a viable role for cyclooxygenase inhibitors in the treatment and prevention of breast cancer, but also raises issues regarding safety and tolerability of these drugs. In this article we discuss the theoretical consequences of cyclooxygenase inhibition, the significance of findings from experimental studies, large scale epidermiological investigations, and the relevance of large population studies of COX-2 inhibitors such as CLASS and VIGOR.     

Diabetes, colorectal cancer and cyclooxygenase 2 inhibition

Diabetes is a risk factor for cancer and specifically colorectal cancer. It is also associated with increased cancer mortality. Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase 2 (Cox-2) inhibitors have been shown to decrease the incidence of colorectal cancer. This effect may be mediated by inhibiting prostaglandin synthesis. Long-term use of high-dose aspirin and NSAIDs is associated with significant gastrointestinal side effects. Unfortunately, the use of Cox-2 inhibitors is associated with an increased incidence of acute myocardial infarction and death from cardiovascular disease. The increased risk of cardiovascular disease in patients with diabetes results in the loss of the potential to use Cox-2 inhibitors for cancer chemoprophylaxis. Until a safer type of Cox-2 inhibitor is available, or low-dose aspirin is evaluated for chemoprophylaxis, a more intense screening programme for colorectal cancer may be appropriate for patients with diabetes, especially men. Healthcare professionals managing patients with diabetes should be aware of the increased risk of this type of cancer.     

The human pharmacology of monocyte cyclooxygenase 2 inhibition by cortisol and synthetic glucocorticoids.

BACKGROUND: We studied the concentration dependence of the inhibitory effects of cortisol, 6-methylprednisolone, and dexamethasone on cyclooxygenase-2 (COX-2) expression and activity in human monocytes in response to lipopolysaccharide (LPS) in vitro. Moreover, we characterized the time and dose dependence of the inhibitory effects of 6-methylprednisolone, administered to healthy subjects, on LPS-inducible prostaglandin E2 (PGE2) biosynthesis in whole blood ex vivo. METHODS: Heparinized whole-blood samples obtained from healthy subjects and patients with rheumatoid arthritis were incubated with LPS (10 microg/ml) for 24 hours at 37 degrees C, and PGE2 was measured in plasma as an index of monocyte COX-2 activity. Comparative experiments were performed in LPS-stimulated isolated monocytes. The levels of COX-2-like immunoreactivity in monocyte lysates were measured by a specific Western blot technique. PGE2 was evaluated by radioimmunoassay. RESULTS: Nanomolar concentrations of cortisol, 6-methylprednisolone, and dexamethasone suppressed LPS-induced PGE2 biosynthesis both in whole blood and in isolated monocytes in vitro with relative potencies similar to those reported for their anti-inflammatory effects in vivo. The administration of single oral doses (4, 8, or 16 mg) of 6-methylprednisolone caused a dose- and time-dependent inhibition of whole-blood COX-2 activity. Whole-blood samples obtained from patients with rheumatoid arthritis treated with comparable maintenance doses of glucocorticoids produced significantly lower levels of LPS-inducible PGE2 than were found in untreated patients. CONCLUSIONS: Therapeutic plasma levels of synthetic glucocorticoids down-regulate inducible prostanoid biosynthesis in circulating monocytes. This effect may represent a readily measurable surrogate marker of their clinical efficacy for dose-finding studies.     

Altering gender role expectations: effects on pain tolerance, pain threshold, and pain ratings.

The literature demonstrating sex differences in pain is sizable. Most explanations for these differences have focused on biologic mechanisms, and only a few studies have examined social learning. The purpose of this study was to examine the contribution of gender-role stereotypes to sex differences in pain. This study used experimental manipulation of gender-role expectations for men and women. One hundred twenty students participated in the cold pressor task. Before the pain task, participants were given 1 of 3 instructional sets: no expectation, 30-second performance expectation, or a 90-second performance expectation. Pain ratings, threshold, and tolerance were recorded. Significant sex differences in the "no expectation" condition for pain tolerance (t = 2.32, df = 38, P <.05) and post-cold pressor pain ratings (t = 2.6, df = 37, P <.05) were found. Women had briefer tolerance times and higher post-cold pressor ratings than men. When given gender-specific tolerance expectations, men and women did not differ in their pain tolerance, pain threshold, or pain ratings. This is the first empirical study to show that manipulation of expectations alters sex differences in laboratory pain.     

Selective inhibition of potassium currents in rat ventricle by clofilium and its tertiary homolog

The effects of clofilium and its tertiary homolog, LY97119 (LY), on K+ currents in isolated ventricular myocytes from adult rat were examined using the whole-cell patch-clamp technique. Acute exposure (less than 30 min) to high concentrations of clofilium (30-100 microM) produced a slowly developing reduction in the peak of the transient outward current (Ito) and an apparent increase in the rate of current inactivation. In addition, inhibition exhibited a marked dependence on the frequency of stimulation (i.e., use-dependent inhibition). For "short" exposure times (i.e., less than 30 min), steady-state inhibition was not attained. Therefore, myocytes were preincubated with clofilium for at least 3 hr before use. Under these conditions, the median inhibitory concentration for steady-state use-dependent inhibition of Ito was 0.5 microM. Recovery of Ito from use-dependent inhibition followed a biexponential time course; tau fast = 75 msec, tau slow = 17 sec. The relative magnitude of the slow component (but not its time constant) increased with higher clofilium concentrations. LY, like clofilium, also induced a time-dependent inhibition of Ito (median inhibiting concentration 0.9 microM). However, unlike clofilium, steady state with LY was reached within 5 min. Furthermore, LY (3 microM) produced very little use-dependent inhibition (29% at 1 Hz compared with 92% for clofilium). This is possibly due to a "fast" unbinding rate upon repolarization (tau = 1.8 s). In contrast to clofilium, LY (1-10 microM) also inhibited the inward rectifier (IK1). The present results suggest that inhibition of Ito may contribute to clofilium's class III antiarrhythmic action.