Adenosine mediates calcium-induced antinociception and potentiation of noradrenergic antinociception in the spinal cord.
Intrathecal (i.t.) coadministration of calcium (Ca2+), 50 micrograms potentiates the spinal antinociceptive action of morphine and noradrenaline (NA) but not cyclohexyladenosine, 5'-N-ethylcarboxamido adenosine or 5-hydroxytryptamine in the rat tail flick test. This dose of Ca2+ has no intrinsic effect in this test. Higher doses of Ca2+ (200-400 micrograms) produce antinociception in the tail flick and hot plate tests, which is completely blocked by pretreatment with the adenosine receptor antagonists theophylline, 50 micrograms and 8-phenyltheophylline, 3 micrograms. 8-Phenyltheophylline also eliminates potentiation of the antinociceptive action of NA by 50 micrograms Ca2+. The intrinsic antinociceptive effect of Ca2+ is blocked by i.t. pretreatment with the neurotoxins capsaicin, 50 micrograms and 6-hydroxydopamine, 50 micrograms but not 5,7-dihydroxytryptamine, 50 micrograms. Antinociception also is blocked by pretreatment with phentolamine but not by methysergide. These results suggest that the antinociceptive action of high doses of Ca2+ is due to release of adenosine (or a nucleotide which is metabolized to adenosine) from the spinal cord. At lower doses, the release of adenosine is insufficient to cause antinociception, but potentiates the action of NA. Adenosine appears to originate from capsaicin-sensitive small diameter primary afferent nerve terminals. A subsequent interaction of adenosine with spinal adrenergic receptors contributes to antinociception.
Sawynok
J
J
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Reid
A
A
Isbrucker
R
R
D015116:5,7-Dihydroxytryptamine; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D004357:Drug Synergism; D006358:Hot Temperature; D006892:Hydroxydopamines / Q000494:pharmacology; D008297:Male; D008784:Methysergide / Q000494:pharmacology; D009638:Norepinephrine; D016627:Oxidopamine; D010146:Pain / Q000503:physiopathology*; D010646:Phentolamine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011983:Receptors, Purinergic / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology
D006892:Hydroxydopamines; D011983:Receptors, Purinergic; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D019830:Adenosine-5'-(N-ethylcarboxamide); C027513:N(6)-cyclohexyladenosine; D016627:Oxidopamine; D013806:Theophylline; C028322:8-phenyltheophylline; D000241:Adenosine; D002118:Calcium; D009638:Norepinephrine; D008784:Methysergide; D010646:Phentolamine