title: Deletion of the CCK2 receptor gene reduces mechanical sensitivity and abolishes the development of hyperalgesia in mononeuropathic mice.
abstract: Previous studies suggest that cholecystokinin (CCK) is implicated in the modulation of pain sensitivity and the development of neuropathic pain. We used CCK(2) receptor deficient (CCK(2) (-/-)) mice and assessed their mechanical sensitivity using Von Frey filaments, as well as the development and time course of mechanical hyperalgesia in a model of neuropathic pain. We found that CCK(2) (-/-) mice displayed mechanical hyposensitivity, which was reversed to the level of wild-type animals after administration of naloxone (0.1-10 mg/kg). On the other hand, injection of L-365260 (0.01-1 mg/kg), an antagonist of CCK(2) receptors, decreased dose-dependently, mechanical sensitivity in wild-type mice. The mechanism of reduced mechanical sensitivity in CCK(2) (-/-) mice may be explained by changes in interactions between CCK and opioid systems. Indeed, CCK(2) (-/-) mice natively expressed higher levels of lumbar CCK(1), opioid delta and kappa receptors. Next, we found that CCK(2) (-/-) mice did not develop mechanical hyperalgesia in the Bennett's neuropathic pain model. Induction of neuropathy resulted in decrease of lumbar pro-opiomelanocortin (POMC) gene expression in wild-type mice, but increase of POMC expression in CCK(2) (-/-) mice. In addition, induction of neuropathy resulted in further increase of opioid delta receptor in CCK(2) (-/-) mice. Gene expression results indicate up-regulation of opioid system in CCK(2) (-/-) mice, which apparently result in decreased neuropathy score. Our study suggests that not only pain sensitivity, but also mechanical sensitivity and the development of neuropathic pain are regulated by antagonistic interactions between CCK and opioid systems.
authors.affiliation: Department of Physiology, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia.
authors.forename: Kaido
authors.initials: K
authors.lastname: Kurrikoff
authors.forename: Sulev
authors.initials: S
authors.lastname: Kõks
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Matsui
authors.forename: Michel
authors.initials: M
authors.lastname: Bourin
authors.forename: Andres
authors.initials: A
authors.lastname: Arend
authors.forename: Marina
authors.initials: M
authors.lastname: Aunapuu
authors.forename: Eero
authors.initials: E
authors.lastname: Vasar
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000235:genetics / Q000378:metabolism; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D006930:Hyperalgesia / Q000188:drug therapy / Q000235:genetics*; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D008026:Ligation / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009270:Naloxone / Q000494:pharmacology / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D010671:Phenylurea Compounds / Q000494:pharmacology; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D043887:Receptor, Cholecystokinin B / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors; D011957:Receptors, Opioid / Q000145:classification / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D013997:Time Factors
chemical_list: D001570:Benzodiazepinones; D004745:Enkephalins; D009292:Narcotic Antagonists; D010671:Phenylurea Compounds; D011498:Protein Precursors; D012333:RNA, Messenger; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D011957:Receptors, Opioid; C029992:proenkephalin; D009270:Naloxone; C058121:L 365260; D011333:Pro-Opiomelanocortin; D004399:Dynorphins