Inhibitory control of the acute mu-withdrawal response by indirectly activated adenosine A1 and kappa-opioid systems in the Guinea-pig ileum; reversal by cholecystokinin.

In the isolated guinea-pig ileum (GPI), the acute mu-opioid withdrawal response is inhibited by the kappa-opioid system, indirectly activated by the opioid agonist; yet, other inhibitory mechanisms are probably operating. On the other hand, cholecystokinin (CCK-8) strongly enhances the withdrawal response. In this study, we have shown that the adenosine A1 antagonist 8-cyclopenthyl-1,3-dimethylxantine (CPT) increased the withdrawal response in dermorphin/naloxone (NLX) tests but lacked any effect if the withdrawal tests were carried out in presence of CCK-8. In tissue preparations coming from a same animal both CPT and the kappa-opioid antagonist, nor-binaltorphimine (BNI), increased the intensity of the withdrawal responses; the effects of the two antagonists were additive. The intensity of withdrawal contractile responses in presence of CCK-8 was similar to those obtained in presence of the two antagonists. Tissue preparations tested with dermorphin/CCK-8/NLX and then washed out yielded contractile responses when subsequently challenged with CPT, BNI or BNI+CPT, with a percentage markedly higher than the percentage of the response to NLX challenge. BNI+CPT also increased the intensity of the response to NLX challenge. These data suggest that acute exposure of GPI to dermorphin induces the activation of both the adenosine A1 and kappa-opioid systems, which in turns inhibit the mu-withdrawal response. CCK-8 antagonises the inhibitory effect of the indirectly activated systems.

Involvement of the cannabinoid CB1 receptor in the opioid inhibition of the response to cholecystokinin and acute withdrawal response.

Numerous recent studies have reported major functional interactions between cannabinoid and opioid systems. These interactions can be studied in the myenteric plexus-longitudinal muscle isolated preparations. We had previously shown that in the guinea-pig ileum (GPI), the opioid acute withdrawal response is under the inhibitory control of several systems; mu-opioid agonist exposure indirectly activates the kappa-opioid system; conversely, exposure to a kappa-opioid agonist indirectly activates the mu-system; the indirectly activated opioid system inhibits the withdrawal response. The adenosine A1 system is also indirectly activated by opioids and it inhibits the withdrawal response. We had also shown that indirect activation is prevented or antagonized by cholecystokinin (CCK-8). In GPI preparations briefly exposed to the mu-agonist, dermorphine (DERM) and then challenged with naloxone (NL), the cannabinoid CB1 antagonist, SR141716 (SR), increased the withdrawal responses to NL, but only did so in presence of a kappa-opioid and an adenosine A(1) antagonist. Under similar experimental conditions, SR also enhances the kappa-opioid withdrawal response. In opioid agonist/CCK-8/NL tests, SR antagonized the inhibition of the tissue response to CCK-8 induced by the mu- or kappa-opioid agonist and increased the kappa-withdrawal response, but not the mu-withdrawal response. However, the dose-response curve against dermorphine inhibition of the response to CCK-8 was bell-shaped and the highest SR concentration also significantly decreased the mu-withdrawal response. In preparations exposed to dermorphine or to the kappa-agonist, U-50,488H, the cannabinoid agonist WIN 55,212-2 increased the opioid-induced inhibition of the tissue response to CCK-8 and decreased the NL-induced responses. These results show that opioid exposure may also activate the cannabinoid CB1 system, which leads to an inhibition of the opioid acute withdrawal response. This phenomenon and the antagonistic effect of SR on the opioid-induced inhibition of the response to CCK-8 suggest that reciprocal interaction between opioid and cannabinoid systems are operating in the enteric nervous system.

Effects of insulin-induced acute hypoglycemia and normoglycemic hyperinsulinemia on the retinal uptake and ocular metabolism of glucose in rabbits.

Glucose is the principal metabolic substrate for the retina in mammals, being essential for maintaining the functional activity of the retina; it can be supplied to the tissue by both vitreous humor and blood. Yet, the impact of hypoglycemia on retinal glucose metabolism has been poorly investigated. We have therefore studied the effects of acute insulin-induced hypoglycemia on the glucose uptake and metabolism in the retina, by analyzing the hypoglycemia-induced changes in the ocular distribution and metabolic fate of [3H]-2-deoxy-D-glucose (2-DG) and [14C]-D-glucose, both injected in the vitreous body. Rabbits were rendered hypoglycemic by subcutaneous injection of insulin (0.8 and 1.2 IU/kg). Insulin-induced hypoglycemia increased both retinal [3H]-radioactivity levels and retina to vitreous humor ratio of [3H]-radioactivity levels ([3H]-[R/VH]). Radio-chromatography showed that hypoglycemia did not induce any change in the retinal conversion of 2-DG to 2-DG-6-phosphate, but increased the conversion of [14C]-D-glucose to [14C]-lactate. Normoglycemic hyperinsulinemia caused no change in either retinal [3H]-radioactivity levels or [3H]-[R/VH] while decreasing retinal [14C]-radioactivity levels and retina to vitreous ratios of 14C-radioactivity levels. These results indicate that acute hypoglycemia increases the uptake rate of glucose by the retina and suggest that normoglycemic hyperinsulinemia may decrease retinal lactate, possibly stimulating its removal from the retina.