Amitriptyline produces multiple influences on the peripheral enhancement of nociception by P2X receptors

Peripherally administered amitriptyline exhibits potential to be a locally active analgesic, while ATP augments peripheral nociception by interacting with P2X(3) receptors on sensory afferents. The present study examined the effects of amitriptyline on flinching and biting/licking behaviours and thermal hyperalgesia produced by alphabeta-methylene-ATP (alphabeta-MeATP), a ligand for P2X(3) receptors, following intraplantar administration into the hindpaw of rats. Coadministration of low doses of amitriptyline (up to 100 nmol) with alphabeta-MeATP augmented thermal hyperalgesia and flinching behaviours. The most active dose of amitriptyline (100 nmol) had no intrinsic effect. Augmentation of alphabeta-MeATP actions appears to be due to increased tissue levels of biogenic amines resulting from inhibition of uptake, as phentolamine (alpha(1)/alpha(2)-adrenergic receptor antagonist) and methysergide (5-hydroxytryptamine or 5-HT(1)/5-HT(2) receptor antagonist) inhibit the augmented flinching produced by alphabeta-MeATP/amitriptyline. When noradrenaline and 5-HT were coadministered with alphabeta-MeATP (both increase the effect of alphabeta-MeATP), amitriptyline had no effect on flinching produced by alphabeta-MeATP/noradrenaline but inhibited flinching produced by alphabeta-MeATP/5-HT. In the presence of low concentrations of formalin (0.5%, 1%; which also increase the effect alphabeta-MeATP), amitriptyline inhibited augmented behaviours. Higher doses of amitriptyline (300-1000 nmol) increased thermal thresholds, suppressed thermal hyperalgesia produced by alphabeta-MeATP, and inhibited flinching produced by alphabeta-MeATP. Collectively, these results indicate that amitriptyline produces complex influences on peripheral pain signaling by P2X receptors. Lower doses augment nociception by alphabeta-MeATP (probably by inhibiting noradrenaline and 5-HT uptake) but inhibit alphabeta-MeATP responses in the presence of inflammatory mediators (perhaps reflecting receptor blocking properties); higher doses uniformly inhibit nociception by alphabeta-MeATP (perhaps reflecting local anesthetic properties).