Increased nociceptive response in mice lacking the adenosine A1 receptor.
The role of the adenosine A1 receptor in nociception was assessed using mice lacking the A1 receptor (A1R-/-) and in rats. Under normal conditions, the A1R-/- mice exhibited moderate heat hyperalgesia in comparison to the wild-type mice (A1R+/+). The mechanical and cold sensitivity were unchanged. The antinociceptive effect of morphine given intrathecally (i.t.), but not systemically, was reduced in A1R-/- mice and this reduction in the spinal effect of morphine was not associated with a decrease in binding of the mu-opioid ligand DAMGO in the spinal cord. A1R-/- mice also exhibited hypersensitivity to heat, but not mechanical stimuli, after localized inflammation induced by carrageenan. In mice with photochemically induced partial sciatic nerve injury, the neuropathic pain-like behavioral response to heat or cold stimulation were significantly increased in the A1R-/-mice. Peripheral nerve injury did not change the level of adenosine A1 receptor in the dorsal spinal cord in rats and i.t. administration of R-PIA effectively alleviated pain-like behaviors after partial nerve injury in rats and in C57/BL/6 mice. Taken together, these data suggest that the adenosine A1 receptor plays a physiological role in inhibiting nociceptive input at the spinal level in mice. The C-fiber input mediating noxious heat is inhibited more than other inputs. A1 receptors also contribute to the antinociceptive effect of spinal morphine. Selective A1 receptor agonists may be tested clinically as analgesics, particularly under conditions of neuropathic pain.
Wu
Wei-Ping
WP
Department of Neurotec, Division of Clinical Neurophysiology, Karolinska Institutet, Karolinska University Hospital-Huddinge, S-141 86 Stockholm, Sweden Department of Physiology and Pharmacology, Section of Molecular Neuropharmacology, Karolinska Institutet, S-141 86 Stockholm, Sweden Department of Pharmacology, College of Pharmacy, Oregon State University, Corvallis, OR 97311-3507, USA.
Hao
Jing-Xia
JX
Halldner
Linda
L
Lövdahl
Cecilia
C
DeLander
Gary E
GE
Wiesenfeld-Hallin
Zsuzsanna
Z
Fredholm
Bertil B
BB
Xu
Xiao-Jun
XJ
D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D000701:Analgesics, Opioid / Q000008:administration & dosage; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005260:Female; D007839:Functional Laterality / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000502:physiology*; D009020:Morphine / Q000008:administration & dosage; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D010147:Pain Measurement; D010777:Photochemistry / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D043682:Receptor, Adenosine A1 / Q000172:deficiency* / Q000235:genetics; D012585:Sciatica / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D018709:Statistics, Nonparametric; D013997:Time Factors; D014970:Xanthines / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D000701:Analgesics, Opioid; D043682:Receptor, Adenosine A1; D014970:Xanthines; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine; C051360:1,3-dipropyl-8-cyclopentylxanthine