Neuropharmacology and analgesiaSpinal serotonin 5-HT7 and adenosine A1 receptors, as well as peripheral adenosine A1 receptors, are involved in antinociception by systemically administered amitriptyline

The present study explored a link between spinal 5-HT7 and adenosine A1 receptors in antinociception by systemic amitriptyline in normal and adenosine A1 receptor knock-out mice using the 2% formalin test. In normal mice, antinociception by systemic amitriptyline 3 mg/kg was blocked by intrathecal administration of the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) 10 nmol. Blockade was also seen in adenosine A1 receptor +/+ mice, but not in −/− mice lacking these receptors. In both normal and adenosine A1 receptor +/+ mice, the selective 5-HT7 receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride (SB269970) 3 μg blocked antinociception by systemic amitriptyline, but it did not prevent antinociception in adenosine A1 receptor −/− mice. In normal mice, flinching was unaltered when the selective 5-HT7 receptor agonist (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin (AS-19) 20 μg was administered alone, but increased when co-administered intrathecally with DPCPX 10 nmol or SB269970 3 μg. Intrathecal AS-19 decreased flinching in adenosine A1 receptor +/+ mice compared to −/− mice. Systemic amitriptyline appears to reduce nociception by activating spinal adenosine A1 receptors secondarily to 5-HT7 receptors. Spinal actions constitute only one aspect of antinociception by amitriptyline, as intraplantar DPCPX 10 nmol blocked antinociception by systemic amitriptyline in normal and adenosine A1 receptor +/+, but not −/− mice. Adenosine A1 receptor interactions are worthy of attention, as chronic oral caffeine (0.1, 0.3 g/L, doses considered relevant to human intake levels) blocked antinociception by systemic amitriptyline in normal mice. In conclusion, adenosine A1 receptors contribute to antinociception by systemic amitriptyline in both spinal and peripheral compartments.