title: Selective impairment of spinal mu-opioid receptor mechanism by plasticity of serotonergic facilitation mediated by 5-HT2A and 5-HT2B receptors.
abstract: Opioid analgesia is compromised by intracellular mediators such as protein kinase C (PKC). The phosphatidylinositol hydrolysis-coupled serotonin receptor 5-HT2 is ideally suited to promote PKC activation. We test the hypothesis that 5-HT2A and 5-HT2B receptors, which have been previously shown to become pro-excitatory after spinal nerve ligation (SNL), can negatively influence the ability of opioids to depress spinal excitation evoked by noxious input. Spinal superfusion with (100 nM) mu-opioid receptor (MOR)-agonist DAMGO significantly depressed C fiber-evoked spinal field potentials. Simultaneous administration of subclinical 5-HT2AR antagonist 4F 4PP (100 nM) or 5-HT2BR antagonist SB 204741 (100 nM) significantly reduced the IC50 value for DAMGO in nerve-ligated rats (97.56 nM ± 1.51 and 1.20 nM ± 1.28 respectively, relative to 104 nM ± 1.08 at the baseline condition), but not in sham-operated rats. Both antagonists failed to alter depression induced by delta-opioid receptor (DOR)-agonist D-ala2-deltorphin II after SNL as well as in the sham condition. Western blot analysis of dorsal horn homogenates revealed bilateral upregulation of 5-HT2AR and 5-HT2BR protein band densities after SNL. As assessed from double immunofluorescence labeling for confocal laser scanning microscopy, scarce dorsal horn cell processes showed co-localization color overlay for 5-HT2AR/MOR, 5-HT2BR/MOR, 5-HT2AR/DOR, or 5-HT2BR/DOR in sham-operated rats. Intensity correlation-based analyses showed significant increases in 5-HT2AR/MOR and 5-HT2BR/MOR co-localizations after SNL. These results indicate that plasticity of spinal serotonergic neurotransmission can selectively reduce spinal MOR mechanisms via 5-HT2A and 5-HT2B receptors, including upregulation of the latter and increased expression in dorsal horn neurons containing MOR.
authors.affiliation: Department of Neurosciences, School of Medicine and Dentistry, University of the Basque Country, Leioa, Spain Department of Neurosciences, School of Pharmacy, University of the Basque Country, Vitoria-Gasteiz, Spain Department of Surgery, Radiology and Physical Medicine, University of the Basque Country, Bilbao, Spain Department of Preventive Medicine and Public Health, School of Medicine and Dentistry, University of the Basque Country, Leioa, Spain.
authors.forename: Zigor
authors.initials: Z
authors.lastname: Aira
authors.forename: Itsaso
authors.initials: I
authors.lastname: Buesa
authors.forename: Gontzal García
authors.initials: GG
authors.lastname: Del Caño
authors.forename: Monika
authors.initials: M
authors.lastname: Salgueiro
authors.forename: Nahia
authors.initials: N
authors.lastname: Mendiable
authors.forename: Janire
authors.initials: J
authors.lastname: Mingo
authors.forename: Luciano
authors.initials: L
authors.lastname: Aguilera
authors.forename: Juan
authors.initials: J
authors.lastname: Bilbao
authors.forename: Jon Jatsu
authors.initials: JJ
authors.lastname: Azkue
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism; D000818:Animals; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology*; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D013116:Spinal Cord / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D017450:Receptors, Opioid, mu; D058830:Serotonin 5-HT2 Receptor Antagonists; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-