ABSTRACT

No abstract

Diabetes can induce a bewildering list of sensory changes, including alteration in pain sensitivity. Painful diabetic neuropathy is refractory to most common analgesics. This study examined the effect of a p38alpha MAPK inhibitor, SD-282, on mechanical allodynia, thermal hyperalgesia, and formalin-evoked nociception in streptozotocin-induced diabetic rats. Four-week diabetic rats exhibited mechanical allodynia, decreased mechanical thresholds, and C- and Adelta-fiber mediated thermal hyperalgesia. Mechanical and thermal responses were measured in diabetic rats following acute and repeated intraperitoneal administration of vehicle, 15 or 45 mg/kg SD-282. Mechanical allodynia was reversed by acute and repeated administration of 15 and 45 mg/kg SD-282. Repeated administration of 15 or 45 mg/kg SD-282 prevented the exacerbation of C-, but not Adelta-fiber, mediated thermal hyperalgesia. Repeated administration of 45 mg/kg SD-282 attenuated flinching behaviors during the quiescent period and the second phase of the formalin response in diabetic rats. Acute and repeated administration of 15 or 45 mg/kg SD-282 had no effect on mechanical, thermal or formalin responses in age-matched control rats. These results indicate a potential therapeutic value of p38alpha MAPK inhibitors in the treatment of aberrant pain sensitivity produced by diabetes.

p38, a mitogen-activated protein kinase, is a major intracellular signaling molecule involved in inflammation. To test the hypothesis that p38 mediates renal disease progression, we administered a novel p38 alpha inhibitor, NPC31169, to rats with remnant kidneys (RKs). RK rats showed increased p38 activation at 9 weeks (by p38 kinase assay), which was blocked by the inhibitor. In contrast to our expectation, treatment with the NPC31169 resulted in worse renal function, more proteinuria, and more severe glomerulosclerosis and tubulointerstitial injury. p38 inhibition resulted in marked cell proliferation in RK rats, with more proliferating tubular cells, myofibroblasts, and macrophages. In contrast, p38 suppression resulted in less tubular cell apoptosis. Interestingly, Western blot demonstrated increased ERK1/2 phosphorylation in p38-treated rats. No histological changes were observed in p38 inhibited sham-operated rats. Our findings indicate that, whereas blocking p38 usually shows benefit in inflammatory disease, in this model p38 inhibition resulted in accelerated renal progression. We conclude that blocking p38-dependent inflammation may have resulted in enhanced proliferation and increased ERK1/2 activation, and thereby explains the worse renal lesions observed.

The role of endogenous opioid peptides (EOP) in the neuroendocrine control of primate gonadotropin and PRL secretion was studied in nonrestrained adult male rhesus monkeys. Morphine (0.5-1.0 mg/kg) was used as the prototype opiate, beta-endorphin (beta-END; 10-20 micrograms/kg) and [D-Ala2,D-Leu5] enkephalin (DADLE; 5-20 micrograms/kg) were used as representatives of EOP, and naloxone (0.5-2.0 mg/kg) was used as an opiate receptor blocker. Drugs were administered and blood was collected (at 20-min intervals for 4 h) through an indwelling jugular catheter. LH and PRL levels were measured in plasma by RIA. Intravenous administration of morphine (1.0 mg/kg) and DADLE (10 micrograms/kg) produced decreases in LH levels of 64% and 40%, respectively. These decreases occurred within 1 h after drug injections and lasted for approximately 3 h. beta-END had no effect on LH levels. Naloxone, at all doses studied, significantly increased LH levels (5- to 8-fold). The LH rises occurred within 20 min and lasted for up to 2 h. Both morphine and beta-END produced immediate increases in PRL, which remained elevated for 3 h. DADLE did not alter PRL levels. Naloxone (1.0 and 2.0 mg/kg) decreased PRL concentrations (45% and 60%, respectively). Pretreatment with morphine or DADLE did not alter the LH response to GnRH (100 micrograms) stimulation, indicating a hypothalamic site of action for the opioid inhibition of LH release. Naloxone administration reversed the inhibitory effects of morphine and DADLE on LH. The stimulatory effect of morphine on PRL levels was also reversed by naloxone. These studies further define the postulated physiological role of EOP in primate reproductive neuroendocrinology. Based on receptor selectivities of these opioid agonists, the inhibition of LH may be mediated by delta-receptors, whereas PRL release appears to be mu-mediated.