A variety of reports describe as a potent antinociceptive agent at spinal sites. Investigations in our laboratory and others show that opioid- induced adenosine release may be one mechanism by which opioids induce antinociception. The role of adenosine in antinociception induced by morphine injected i.t. has been the subject of several studies, but our results suggest adenosine is also involved in descending systems activated by morphine injected i.c.v. to induce antinociception. Based on preliminary results, our working hypothesis is that adenosine plays an important role in mechanisms of opioid (i.c.v.)-induced antinociception. The goal of our proposed studies is to determine the significance of adenosine in mechanisms of antinociception induced by interactions at specific opioid receptors and to determine the site and stimulus of adenosine release following opioid administration. Behavioral assays for antinociception will be used to determine interactions between selective opioid agonists and adenosine agonists or antagonists. Precedent already exists for unique activation of descending systems via interactions at specific opioid receptors. These investigations will determine whether adenosine release is a mechanism common to interactions at all opioid receptor types. Direct biochemical measurement of adenosine release will be used to reveal sites of adenosine release following opioid injections. Animals are pretreated with selective neurotoxins to lesion specific spinal systems and adenosine release stimulated by opioids in control animals is compared to release in neurotoxin treated animals. Design of these experiments will allow us to determine the site of adenosine release and provide preliminary information as to the neurocicuitry of spinal systems mediating antinociception. The significance of spinal sites in mechanisms of antinociception is well established. The proposed studies utilize an appropriate mix of behavioral and biochemical techniques to improve our understanding of how and where spinal adenosine participates in basic mechanisms of antinociception.
| Keil 2nd, G J; DeLander, G E (1996) Altered sensory behaviors in mice following manipulation of endogenous spinal adenosine neurotransmission. Eur J Pharmacol 312:7-14 |
| Keil 2nd, G J; Delander, G E (1995) Time-dependent antinociceptive interactions between opioids and nucleoside transport inhibitors. J Pharmacol Exp Ther 274:1387-92 |
| Keil 2nd, G J; DeLander, G E (1994) Adenosine kinase and adenosine deaminase inhibition modulate spinal adenosine- and opioid agonist-induced antinociception in mice. Eur J Pharmacol 271:37-46 |
| De Lander, G E; Keil 2nd, G J (1994) Antinociception induced by intrathecal coadministration of selective adenosine receptor and selective opioid receptor agonists in mice. J Pharmacol Exp Ther 268:943-51 |
| Keil 2nd, G J; DeLander, G E (1992) Spinally-mediated antinociception is induced in mice by an adenosine kinase-, but not by an adenosine deaminase-, inhibitor. Life Sci 51:PL171-6 |
