title: Effects of centrally acting analgesics on spinal segmental reflexes and wind-up.
abstract: BACKGROUND
  The spinal cord is a prime site of action for analgesia. Here we characterize the effects of established analgesics on segmental spinal reflexes. The aim of the study was to look for the pattern of action or signature of analgesic effects on these reflexes.
  
  
  METHODS
  We used a spinal cord in vitro preparation of neonate mice to record ventral root responses to dorsal root stimulation. Pregabalin, clonidine, morphine and duloxetine and an experimental sigma-1 receptor antagonist (S1RA) were applied to the preparation in a cumulative concentration protocol. Drug effects on the wind-up produced by repetitive stimulation of C-fibres and on responses to single A- and C-fibre intensity stimuli were analysed.
  
  
  RESULTS
  All compounds produced a concentration-dependent inhibition of total spikes elicited by repetitive stimulation. Concentrations producing ∼50% reduction in this parameter were (in μM) clonidine (0.01), morphine (0.1), pregabalin (1), duloxetine (10) and S1RA (30). At these concentrations clonidine, pregabalin and S1RA had significant effects on the wind-up index and little depressant effects on responses to single stimuli. Morphine and duloxetine did not depress wind-up index and showed large effects on responses to single stimuli. None of the compounds had strong effects on the amplitude of the non-nociceptive monosynaptic reflex.
  
  
  CONCLUSIONS
  morphine and duloxetine had general depressant effects on spinal reflexes, whereas the effects of clonidine, pregabalin and S1RA appeared to be restricted to signals originated by strong repetitive activation of C-fibres. Results are discussed in the context of reported behavioural effects of the compounds studied.
authors.affiliation: Department of Systems Biology (Division Physiology), Edificio Medicina, Universidad de Alcala, Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Mazo
authors.affiliation: Department of Systems Biology (Division Physiology), Edificio Medicina, Universidad de Alcala, Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Roza
authors.affiliation: Esteve, Drug Discovery and Preclinical Development, Parc Científic de Barcelona, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Zamanillo
authors.affiliation: Esteve, Drug Discovery and Preclinical Development, Parc Científic de Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Merlos
authors.affiliation: Esteve, Drug Discovery and Preclinical Development, Parc Científic de Barcelona, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Vela
authors.affiliation: Department of Systems Biology (Division Physiology), Edificio Medicina, Universidad de Alcala, Madrid, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Lopez-Garcia
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000187:drug effects; D009413:Nerve Fibers, Myelinated / Q000187:drug effects; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects; D059225:Nociception / Q000187:drug effects*; D017480:Receptors, sigma / Q000187:drug effects; D012023:Reflex, Monosynaptic / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects*; D013126:Spinal Nerve Roots / Q000187:drug effects; D000097605:Sigma-1 Receptor
chemical_list: D000700:Analgesics; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor