title: Increased spinal cholecystokinin activity after systemic resiniferatoxin: electrophysiological and in situ hybridization studies.
abstract: The present study assessed the effect of a single subcutaneous injection of resiniferatoxin (RTX), an ultrapotent capsaicin analogue, on the activity of spinal cholecystokinin (CCK) systems, by using electrophysiological and in situ hybridization techniques. Subcutaneous RTX at 0.3 mg/kg, but not vehicle, produced marked thermal hypoalgesia in rats on the hot plate and tail flick tests. Partial recovery from hypoalgesia occurred in some (<50%), but not all, RTX-treated rats after 2 weeks. The flexor reflex in response to activation of high threshold afferents was recorded 15-35 days after RTX- or vehicle-treatment. There was no obvious difference between RTX- and vehicle-treated rats in the baseline flexor reflex. Intravenous morphine at 1 mg/kg caused a depression of the flexor reflex in vehicle- and in RTX-treated rats. The reflex depressive effect of morphine was significantly briefer in RTX-treated, non-recovered rats than vehicle-treated rats. Furthermore, CI-988, a high affinity antagonist of CCKB receptors, caused a minor depression of the reflex in vehicle- and RTX-treated rats that had partially recovered, whereas the reflex depressive effect of CI-988 was significantly enhanced in RTX-treated, non-recovered rats. In situ hybridization showed that RTX treatment caused a marked and significant increase in the number of dorsal root ganglion (DRG) neurone profiles expressing CCKB receptor mRNA, whereas only a small increase was observed for CCKA receptor mRNA expressing neurone profiles. Significantly more DRG neurone profiles expressed CCKB receptor mRNA in RTX-treated, non-recovered rats compared to partially recovered rats. RTX-treatment did not influence the expression of CCK mRNA in DRGs. Since CCK functions as a physiological antagonist of morphine, it is suggested that RTX treatment enhances the activity of spinal CCK systems, leading to the reduced effect of morphine and increased effect of the CCKB receptor antagonist CI-988. This may mainly be due to upregulation of CCKB receptors in DRG neurones.
authors.affiliation: Department of Neuroscience, Karolinska Institute, Stockholm, Sweden Department of Physiology and Pharmacology, Division of Pharmacology, Karolinska Institute, Stockholm, Sweden Department of Medical Laboratory Sciences and Technology, Division of Clinical Neurophysiology, Karolinska Institute, Huddinge, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Broberger
authors.forename: Tünde
authors.initials: T
authors.lastname: Farkas-Szallasi
authors.forename: Arpad
authors.initials: A
authors.lastname: Szallasi
authors.forename: Jan M
authors.initials: JM
authors.lastname: Lundberg
authors.forename: Tomas
authors.initials: T
authors.lastname: Hökfelt
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Wiesenfeld-Hallin
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Xu
mesh_terms: D000818:Animals; D002766:Cholecystokinin / Q000378:metabolism*; D003655:Decerebrate State; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000502:physiology*; D006727:Hormone Antagonists / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007279:Injections, Subcutaneous; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000008:administration & dosage / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors / Q000235:genetics*; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004224:Diterpenes; D006727:Hormone Antagonists; D007211:Indoles; D009498:Neurotoxins; D012333:RNA, Messenger; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C065599:PD 134308; D008536:Meglumine; D009020:Morphine; D002766:Cholecystokinin; C024353:resiniferatoxin