Dissociation of rewarding,anti‐aversive and anti‐nociceptive effects of different classes of anti‐nociceptives in the rat

It was previously shown that morphine more potently reduces the affective as compared to the sensory component of nociception, and this effect is independent of morphine's rewarding properties. Here we investigated whether this finding can be generalized to other classes of anti‐nociceptive drugs. The effect of oxycodone (0–10 mg/kg, i.p.), tramadol (0–10 mg/kg, i.p.), ibuprofen (0–300 mg/kg, i.p.) and pregabalin (0–31.6 mg/kg, i.p.) on negative affect and mechanical hypersensitivity accompanying carrageenan‐induced (0.5% intraplantar) inflammatory nociception was assessed using conditioned place aversion (CPA) and Randall Selitto paw pressure test, respectively. The rewarding effect of these drugs was assessed using conditioned place preference (CPP). All four anti‐nociceptive drugs dose‐dependently reduced carrageenan‐induced CPA and mechanical hypersensitivity. Furthermore all drugs induced CPP, except for ibuprofen. Similar to morphine, oxycodone and tramadol showed a large dissociation of anti‐aversive versus anti‐nociceptive potency, i.e. 10 times more potent against the affective versus the sensory component of nociception. Oxycodone and tramadol were 30 and 10 times more potent to produce CPP in animals under normal versus painful conditions. Ibuprofen and pregabalin also showed a dissociation of anti‐aversive and anti‐nociceptive potency, but less pronounced (i.e. three times more potent against the affective component). However, pregabalin showed no dissociation between rewarding potency under normal versus painful conditions. Taken together, these data suggest that the dissociation of rewarding potency in animals under normal versus painful conditions is limited to drugs with an opioid mechanism of action, while the dissociation of anti‐aversive and anti‐nociceptive potency applies to anti‐nociceptive drugs with different mechanisms of action.     

The potential anti‐xanthoma and anti‐atherosclerotic effects of proton pump inhibitors

Xanthoma and atherosclerosis are similar in having infiltrations of macrophages that have transformed into foam cells. The oxidized low‐density lipoprotein (LDL) promotes adhesion of monocytes to endothelial cells by inducing expression of adhesion molecules on vascular endothelial cells. Macrophages transform into foam cells by incorporating oxidized LDL using several kinds of scavenger receptors. Very recently, it has been shown that LDL oxidation occurs within lysosomes in macrophages in atherosclerotic lesions and the increase of intra‐lysosomal PH can prevent LDL oxidation. Given that proton pump inhibitors can decrease the intra‐lysosomal acidicty through inhibition of the lysosomal membrane H+/K+ATPase, theses agents could afford protection against atherosclerosis and xanthoma formation.     

Shear‐aggregated fibronectin with anti‐adhesive properties

Biomaterials based on proteins, such as fibronectin, have the potential to guide cell and tissue behaviour during healing as a function of their unique mechanical and bioactive properties. Fibronectin has been reported as a scaffold for attachment of fibroblasts and subsequent deposition of collagen. We have recently developed a derivative process of shear‐aggregated fibronectin that prevents cell attachment without causing cell death. This has potential applications in clinical situations where adhesions form across gliding surfaces and cause loss of function, e.g. peritoneal or flexor tendon adhesions. This in vitro study tested this derivative fibronectin biomaterial and its effects on aggressive adhesion‐forming cells, using rabbit flexor tendon synovial fibroblasts. We investigated degradation of the novel biomaterial, and attachment of fibroblasts to glass coated with the biomaterial, relative to fibroblast attachment to uncoated and fibronectin‐coated glass. We assessed infiltration of the derivative fibronectin biomaterial by fibroblasts and cytotoxicity of the biomaterial to fibroblasts. The interaction between fibroblasts and the derivative fibronectin biomaterial was visualized using time‐lapse photography. The derivative fibronectin biomaterial dissolved by 88% of its mass by 3 weeks. Fibroblast attachment to the novel biomaterial was significantly reduced at 6 h. After 24 h of exposure to the novel biomaterial, fibroblasts did not migrate into it, there was no cell death and no attachment was seen using time‐lapse. This novel derivative fibronectin biomaterial combines inhibition of fibroblast attachment with barrier effects and has suitable mechanical properties for surgical use in preventing adhesions in vivo. Copyright © 2010 John Wiley & Sons, Ltd.