Intrathecal Tyr-W-MIF-1 produces potent, naloxone-reversible analgesia modulated by alpha(2)-adrenoceptors

Spinal administration of morphine or [D-Ala(2),MePhe(4),Gly(ol)(5))]enkephalin (DAMGO) produces potent, naloxone-reversible analgesia that is modulated by alpha(2)-adrenoceptors. Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2) is a naturally occurring, amidated tetrapeptide that is structurally related to the melanocyte-stimulating hormone release inhibiting factor-1 (MIF-1) family of endogenous peptides. Tyr-W-MIF-1 displays high selectivity for the mu-opioid receptor. We investigated the effect of spinal administration of Tyr-W-MIF-1 on analgesia using the mouse tail-flick assay. Intrathecal (i.t.) administration of Tyr-W-MIF-1 produced a dose-dependent analgesic response, with an ED(50) of 0.41 mu g, that was reversed by naloxone. Pretreatment with the mu-opioid receptor-selective antagonist beta-funaltrexamine blocked the effect of i.t. Tyr-W-MIF-1. However, pretreatment with the mu(1)-opioid receptor-selective antagonist naloxonazine did not antagonize the analgesia, indicating the effect was mediated through spinal mu(2)-opioid receptors. Pretreatment with desipramine, an inhibitor of norepinephrine reuptake, potentiated the analgesic effect of i.t. Tyr-W-MIF-1, producing a 3.1-fold leftward shift in the dose-response curve. Spinal administration of yohimbine, an alpha(2)-adrenoceptor-selective antagonist, significantly attenuated the analgesic effect of Tyr-W-MIF-1. Thus, the potent analgesic effect of i.t. Tyr-W-MIF-1 is mediated through spinal mu(2)-receptors, and is modulated by norepinephrine and alpha(2)-adrenoceptors.