title: Amitriptyline produces multiple influences on the peripheral enhancement of nociception by P2X receptors.
abstract: 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).
authors.affiliation: Department of Pharmacology, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5.
authors.forename: James B
authors.initials: JB
authors.lastname: Waldron
authors.forename: Allison R
authors.initials: AR
authors.lastname: Reid
authors.forename: Jana
authors.initials: J
authors.lastname: Sawynok
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000639:Amitriptyline / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005557:Formaldehyde / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008784:Methysergide / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D010646:Phentolamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058469:Receptors, Purinergic P2X; D012702:Serotonin Antagonists / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D018712:Analgesics, Non-Narcotic; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D012702:Serotonin Antagonists; D000639:Amitriptyline; D005557:Formaldehyde; D000255:Adenosine Triphosphate; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D008784:Methysergide; D010646:Phentolamine