Changes in spinal delta and kappa opioid systems in mice deficient in the A2A receptor gene.
A large body of evidence indicates important interactions between the adenosine and opioid systems in regulating pain at both the spinal and supraspinal level. Mice lacking the A(2A) receptor gene have been developed successfully, and these animals were shown to be hypoalgesic. To investigate whether there are any compensatory alterations in opioid systems in mutant animals, we have performed quantitative autoradiographic mapping of mu, delta, kappa, and opioid receptor-like (ORL1) opioid receptors in the brains and spinal cords of wild-type and homozygous A(2A) receptor knock-out mice. In addition, mu-, delta-, and kappa-mediated antinociception using the tail immersion test was tested in wild-type and homozygous A(2A) receptor knock-out mice. A significant reduction in [3H]deltorphin-I binding to delta receptors and a significant increase in [3H]CI-977 binding to kappa receptors was detected in the spinal cords but not in the brains of the knock-out mice. Mu and ORL1 receptor expression were not altered significantly. Moreover, a significant reduction in delta-mediated antinociception and a significant increase in kappa-mediated antinociception were detected in mutant mice, whereas mu-mediated antinociception was unaffected. Comparison of basal nociceptive latencies showed a significant hypoalgesia in knock-out mice when tested at 55 degrees C but not at 52 degrees C. The results suggest a functional interaction between the spinal delta and kappa opioid and the peripheral adenosine system in the control of pain pathways.
Bailey
Alexis
A
Pharmacology Group, School of Biomedical and Life Sciences, University of Surrey, Guildford, Surrey, GU2 7XH United Kingdom.
Ledent
Catherine
C
Kelly
Mary
M
Hourani
Susanna M O
SM
Kitchen
Ian
I
D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006720:Homozygote; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009294:Narcotics / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D043705:Receptor, Adenosine A2A; D011957:Receptors, Opioid / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D000094942:Nociceptin Receptor
D008024:Ligands; D009294:Narcotics; D043705:Receptor, Adenosine A2A; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D018047:Receptors, Purinergic P1; D000094942:Nociceptin Receptor; C000722287:Oprl1 protein, mouse