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 αβ-methylene-ATP (αβ-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 αβ-MeATP augmented thermal hyperalgesia and flinching behaviours. The most active dose of amitriptyline (100 nmol) had no intrinsic effect. Augmentation of αβ-MeATP actions appears to be due to increased tissue levels of biogenic amines resulting from inhibition of uptake, as phentolamine (α ₁/α ₂-adrenergic receptor antagonist) and methysergide (5-hydroxytryptamine or 5-HT ₁/5-HT ₂ receptor antagonist) inhibit the augmented flinching produced by αβ-MeATP/amitriptyline. When noradrenaline and 5-HT were coadministered with αβ-MeATP (both increase the effect of αβ-MeATP), amitriptyline had no effect on flinching produced by αβ-MeATP/noradrenaline but inhibited flinching produced by αβ-MeATP/5-HT. In the presence of low concentrations of formalin (0.5%, 1%; which also increase the effect αβ-MeATP), amitriptyline inhibited augmented behaviours. Higher doses of amitriptyline (300-1000 nmol) increased thermal thresholds, suppressed thermal hyperalgesia produced by αβ-MeATP, and inhibited flinching produced by αβ-MeATP. Collectively, these results indicate that amitriptyline produces complex influences on peripheral pain signaling by P2X receptors. Lower doses augment nociception by αβ-MeATP (probably by inhibiting noradrenaline and 5-HT uptake) but inhibit αβ-MeATP responses in the presence of inflammatory mediators (perhaps reflecting receptor blocking properties); higher doses uniformly inhibit nociception by αβ-MeATP (perhaps reflecting local anesthetic properties).