European journal of pharmacology
-
The hyperalgesic response to prostaglandin E2 (PGE2) is thought to be mediated by activation of the cAMP/protein kinase A pathway in primary sensory neurones. The aim of this study was to investigate the relative contribution of different PGE2 (EP) receptor subtypes to the overall activity of adenylyl cyclase in adult rat isolated dorsal root ganglion (DRG) cells, in vitro. PGE2 and the prostanoid EP4 receptor agonist ONO-AE1-329 increased [3H]cAMP production with EC50 values of 500 nM and 70 nM, respectively, and showed similar efficacies. ⋯ No evidence for prostanoid EP3 receptor-dependent inhibition of adenylyl cyclase activity could be obtained to account for the relatively weak effect of PGE2 compared with prostacyclin receptor agonists. Interestingly, sulprostone (prostanoid EP3/EP1 receptor agonist) caused a Rho-kinase-dependent retraction of neurites, suggesting an alternative role for prostanoid EP3 receptors in DRG cells. In conclusion, PGE2 mediated increases in adenylyl cyclase activity in primary sensory neurones is likely to be mediated by activation of prostanoid EP4 receptors, and is not under inhibitory control by prostanoid EP3 receptors.
-
We investigated the antinociceptive efficacy of systemic and centrally injected oxycodone on thermal hyperalgesia in streptozotocin-induced diabetic mice. The antinociceptive response was assessed by recording the latency in the tail-flick test using the radiant heat from a 50-W projection bulb on the tail. The tail-flick latency in diabetic mice was significantly shorter than that in non-diabetic mice. ⋯ On the other hand, pretreatment with nor-binaltorphimine practically abolished the antinociceptive effects of both p.o.- and i.t.-administered oxycodone in diabetic mice. Naltrindole, a selective delta-opioid receptor antagonist, had no effects on the antinociceptive effect of oxycodone in either non-diabetic or diabetic mice. These results suggest that the antinociceptive effects of oxycodone may be mediated by spinal kappa-opioid receptors in diabetic mice, whereas it may interact primarily with supraspinal and spinal mu-opioid receptors in non-diabetic mice.
-
Blockades of cytokine and oxygen radicals release are considered to be beneficial in reducing multiple organ injury and increasing the survival rate in sepsis/septic shock. Thus, we examined the protective efficacy of N-allylsecoboldine, a secoaporphine derivative with antioxidant and alpha1-adrenoceptor blocking activities, in rats treated with endotoxin (E. coli lipopolysaccharide, LPS). Pretreatment of LPS-treated rats with N-allylsecoboldine significantly attenuated the late-phase hypotension, hypoglycemia and incremental plasma tumor necrosis factor (TNF)-alpha. ⋯ This study demonstrates N-allylsecoboldine's ability to avail against acute renal failure and increase survival rate during endotoxemia. These beneficial effects may be attributed to the inhibition of iNOS expression, TNF-alpha production, and free radical scavenging activities. However, the role of alpha1-adrenoceptor antagonism for N-allylsecoboldine in sepsis remains unclear.
-
Comparative Study
Antitumour activity of [1,2-di(cyclopentadienyl)-1,2-di(p-N,N-dimethylaminophenyl)-ethanediyl] titanium dichloride in xenografted Ehrlich's ascites tumour.
The effects of a new titanocene compound with an ansa ligand in the cyclopentadienyl rings, the 1,2-di(cyclopentadienyl)-1,2-di(p-N,N-dimethylaminophenyl)-ethanediyl] titanium dichloride (TITANOCENE X), on the growth and differentiation of granulocyte-macrophage progenitor cells [colony-forming unit-granulocyte-macrophage (CFU-GM)] and Natural killer (NK) cell activity in Ehrlich's ascites tumour (EAT)-bearing mice were studied. Myelosuppression concomitant with increased numbers of spleen CFU-GM was observed in tumour-bearing mice. Treatment of these animals with TITANOCENE X (2.5-50 mg/kg/day) produced an increase in myelopoiesis, in a dose-dependent manner, and reduced spleen colony formation. ⋯ In comparison with previous results from our laboratory addressing the effects of titanocenes on haematopoiesis, we observed with TITANOCENE X a similar effective profile as for bis(cyclopentadienyl) dithiocyanate titanium(IV), being both less effective than di(cyclopentadienyl) dichloro titanium(IV), since the latter not only prolonged, but also increased the rate of survival. These differences in efficacy may be due to the nature of the ansa-cyclopentadienyl ligand used in TITANOCENE X, since the C2 bridge between the two cyclopentadienyl groups will increase the hydrolytic stability by an organometallic chelate effect. Also, the introduction of two dimethylamino substituents increases the water solubility of TITANOCENE X when compared to titanocene dichloride itself.
-
The transient receptor potential vanilloid 1 (TRPV1) is an excitatory cation channel, rather selectively expressed in a subpopulation of nociceptive, primary sensory neurons that promote neurogenic inflammation via neuropeptide release. TRPV1 is activated by noxious temperature, low extracellular pH and diverse lipid derivatives, and is uniquely sensitive to vanilloid molecules, including capsaicin. TRPV1 expression and sensitivity is highly regulated by diverse G protein-coupled and tyrosine kinase receptors. ⋯ In the airways, TRPV1 agonists cause cough, bronchoconstriction, microvascular leakage, hyperreactivity and hypersecretion. Patients with asthma and chronic obstructive pulmonary disease are more sensitive to the tussive effect of TRPV1 agonists and TRPV1 activation may contribute to respiratory symptoms caused by acidic media present in the airways during asthma exacerbation, gastroesophageal reflux induced asthma or in other conditions. TRPV1 antagonists may be useful in the treatment of these diseases.