Genetic deletion of the adenosine A(2A) receptor in mice reduces the changes in spinal cord NMDA receptor binding and glucose uptake caused by a nociceptive stimulus.
Mice lacking the adenosine A(2A) receptor are less sensitive to nociceptive stimuli, and A(2A) receptor antagonists have antinociceptive effects. We have previously shown a marked reduction in the behavioural responses to formalin injection in A(2A) receptor knockout mice. This may be due to the presence of pronociceptive A(2A) receptors on sensory nerves, and if so spinal cords from A(2A) receptor knockout mice may have altered neurochemical responses to a nociceptive stimulus. We tested this hypothesis by studying two parameters known to change with spinal cord activity, NMDA glutamate receptor binding and [(14)C]-2-deoxyglucose uptake, following intraplantar formalin injection in wild-type and A(2A) receptor knockout mice. In naïve untreated A(2A) knockout mice [(14)C]-2-deoxyglucose uptake in all regions of the spinal cord was significantly lower compared to the wild-type, similar to the reduced NMDA receptor binding that we have previously observed. Following formalin treatment, there was an decrease in [(3)H]-MK801 binding to NMDA receptors and an increase in [(14)C]-2-deoxyglucose uptake in the spinal cords of wild-type mice, and these changes were significantly reduced in the A(2A) knockout mice. In addition to altered behavioural responses, there are therefore corresponding reductions in spinal cord neurochemical changes induced by formalin in mice lacking adenosine A(2A) receptors. These observations support the hypothesis that activation of A(2A) receptors enhances nociceptive input into the spinal cord and suggests a possible role for A(2A) antagonists as analgesics.
Hussey
M J
MJ
Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK.
Clarke
G D
GD
Ledent
C
C
Kitchen
I
I
Hourani
S M O
SM
D000818:Animals; D003847:Deoxyglucose / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010146:Pain / Q000378:metabolism*; D010147:Pain Measurement; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*
D043705:Receptor, Adenosine A2A; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D003847:Deoxyglucose; D005947:Glucose