title: Genetic inactivation of pleiotrophin but not midkine potentiates clonidine-induced alpha-2 adrenergic-mediated analgesia.
abstract: Genetic deletion of the heparin-binding cytokines pleiotrophin (PTN) or midkine (MK) potentiates morphine-induced antinociceptive effects in animal models. Despite the known interactions between the opioid and noradrenergic systems in the control of pain, the possible roles of PTN and/or MK in analgesia induced by agonists of α2-adrenergic receptors remained to be studied. We have now tested the antinociceptive effects of the α2-adrenergic receptor agonist clonidine in female PTN genetically deficient (PTN-/-), MK genetically deficient (MK-/-) and wild type (WT+/+) mice. We did not find differences among genotypes in the hot-plate test, an assay in which supraspinal and spinal mechanisms contribute to nociceptive responses, suggesting that endogenous expression of PTN and MK is not key in the analgesia induced by clonidine in this test. In contrast, we found that clonidine-induced analgesia was significantly enhanced in PTN-/- mice compared to MK-/- and WT+/+ mice in the tail-immersion test. Interestingly, the α2-adrenergic antagonist yohimbine prevented clonidine-induced analgesia in the tail immersion test in all the 3 genotypes. The data suggest that the spinal antinociceptive effects caused by stimulation of α2-adrenoceptors are differentially regulated by endogenous expression of PTN.
authors.affiliation: Pharmacology lab, Department of Pharmaceutical and Food Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Cta. Boadilla Km. 5300, 28668 Boadilla del Monte, Madrid, Spain. Electronic address: marta.vicenterodriguez@ceu.es.
authors.forename: Marta
authors.initials: M
authors.lastname: Vicente-Rodríguez
authors.forename: Carmen
authors.initials: C
authors.lastname: Pérez-García
authors.forename: Esther
authors.initials: E
authors.lastname: Gramage
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Herradón
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D003000:Clonidine / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000078792:Midkine
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000700:Analgesics; D002352:Carrier Proteins; D016207:Cytokines; C066845:pleiotrophin; D000078792:Midkine; D003000:Clonidine
keywords: Hot plate; Noradrenergic; Pain; Spinal; Tail flick; Yohimbine