title: Synaptic upregulation and superadditive interaction of dopamine D2- and μ-opioid receptors after peripheral nerve injury.
abstract: A sound strategy for improving the clinical efficacy of opioids involves exploiting positive interactions with drugs directed at other targets in pain pathways. The current study investigated the role of dopamine receptor D2 (D2R) in modulation of spinal dorsal horn excitability to noxious input, and interactions therein with μ-opioid receptor (MOR) in an animal model of neuropathic pain induced by spinal nerve ligation (SNL). C-fiber-evoked field potentials in the spinal dorsal horn were depressed concentration dependently by spinal superfusion with the D2R agonist quinpirole both in nerve-injured and sham-operated (control) rats. However, quinpirole-induced depression was significant at 10 μmol/L after SNL but only at 100 μmol/L in control rats. This quinpirole effect was completely abolished by MOR antagonist CTOP at subclinical concentration (1 μmol/L) in nerve-injured rats, but was unaltered in sham-operated rats. Nine days after SNL, D2R was upregulated to both presynaptic and postsynaptic locations in dorsal horn neurons, as revealed by double confocal immunofluorescence stainings for synaptophysin and PSD-95. In addition, D2R/MOR co-localization was increased after SNL. Co-administration of 1 μmol/L quinpirole, insufficient per se to alter evoked potentials, dramatically enhanced inhibition of evoked potentials by MOR agonist DAMGO, reducing the IC50 value of DAMGO by 2 orders of magnitude. The present data provide evidence of profound functional and subcellular changes in D2R-mediated modulation of noxious input after nerve injury, including positive interactions with spinal MOR. These results suggest D2R co-stimulation as a potential avenue to improve MOR analgesia in sustained pain states involving peripheral nerve injury.
authors.affiliation: Department of Neurosciences, School of Medicine and Dentistry, University of the Basque Country, Bilbao, Spain Movement Disorders and Autonomic Unit, Neurology Service, Cruces University Hospital, Basque Health Service (Osakidetza), Spain.
authors.forename: Zigor
authors.initials: Z
authors.lastname: Aira
authors.forename: Teresa
authors.initials: T
authors.lastname: Barrenetxea
authors.forename: Itsaso
authors.initials: I
authors.lastname: Buesa
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Gómez-Esteban
authors.forename: Jon Jatsu
authors.initials: JJ
authors.lastname: Azkue
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D018491:Dopamine Agonists / Q000494:pharmacology; D004558:Electric Stimulation; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology; D059348:Peripheral Nerve Injuries / Q000473:pathology / Q000503:physiopathology*; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D013569:Synapses / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D000701:Analgesics, Opioid; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D018491:Dopamine Agonists; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017448:Receptors, Dopamine D2; D017450:Receptors, Opioid, mu; D016708:Synaptophysin; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; D019257:Quinpirole; D013004:Somatostatin
keywords: Descending pathways; Electrophysiology; Neuropathic pain; Rat