title: Paracetamol fails to positively modulate and directly activate chloride currents in human α1-glycine receptors.
abstract: Paracetamol (acetaminophen) is a widely used antipyretic and analgesic drug for mild or moderate pain states. As the primary site of action of paracetamol is still the subject of ongoing discussion, the focus of this study is the investigation of a potential mechanism which might contribute to its beneficial effects in the therapy of pain. Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. In this study we investigated the interaction of paracetamol with strychnine-sensitive α(1)-glycine receptors (α(1)-GlyR). α(1)-GlyR subunits transiently expressed in HEK-293 cells were studied using the whole-cell patch-clamp technique and a piezo-controlled liquid filament fast application system. Paracetamol fails to show a positive allosteric modulatory effect in low nano- to micromolar concentrations and lacks direct activation in micromolar concentrations at the α(1)-GlyR. Consequently, the analgesic actions of paracetamol leading to pain relief appear to be mediated via other mechanisms, but not via activation of spinal glycinergic pathways.
authors.affiliation: Clinic for Anaesthesia and Critical Care Medicine, OE 8050, Hannover, Germany.
authors.forename: Jeanne
authors.initials: J
authors.lastname: de la Roche
authors.forename: Vanessa
authors.initials: V
authors.lastname: Buchholz
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dengler
authors.forename: Gertrud
authors.initials: G
authors.lastname: Haeseler
authors.forename: Martin
authors.initials: M
authors.lastname: Leuwer
authors.forename: Jörg
authors.initials: J
authors.lastname: Ahrens
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D058633:Antipyretics / Q000494:pharmacology*; D002712:Chlorides / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018684:Glycine Agents / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D009994:Osmolar Concentration; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D018009:Receptors, Glycine / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism; D059010:Single-Cell Analysis
chemical_list: D018712:Analgesics, Non-Narcotic; D058633:Antipyretics; D002712:Chlorides; D018690:Excitatory Amino Acid Agonists; D018684:Glycine Agents; D021122:Protein Subunits; D018009:Receptors, Glycine; D011994:Recombinant Proteins; D000082:Acetaminophen