Intrathecal Tyr-W-MIF-1 produces potent, naloxone-reversible analgesia modulated by alpha 2-adrenoceptors.
Spinal administration of morphine or [D-Ala2,MePhe4,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 ED50 of 0.41 microgram, 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 mu1-opioid receptor-selective antagonist naloxonazine did not antagonize the analgesia, indicating the effect was mediated through spinal mu2-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 mu2-receptors, and is modulated by norepinephrine and alpha 2-adrenoceptors.
Gergen
K A
KA
VA Medical Center, New Orleans, LA, USA.
Zadina
J E
JE
Kastin
A J
AJ
Paul
D
D
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D003891:Desipramine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007278:Injections, Spinal; D009075:MSH Release-Inhibiting Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009270:Naloxone / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D015016:Yohimbine / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D009292:Narcotic Antagonists; D018341:Receptors, Adrenergic, alpha-2; C077532:tyrosyl-prolyl-tryptophyl-glycinamide; D015016:Yohimbine; D009270:Naloxone; D009271:Naltrexone; C024524:beta-funaltrexamine; D009075:MSH Release-Inhibiting Hormone; D003891:Desipramine; D009638:Norepinephrine