Modulation of Glycinergic Neurotransmission may Contribute to the Analgesic Effects of Propacetamol

Abstract

Treating neuropathic pain remains challenging, and therefore new pharmacological strategies are urgently required. Here, the enhancement of glycinergic neurotransmission by either facilitating glycine receptors (GlyR) or inhibiting glycine transporter (GlyT) function to increase extracellular glycine concentration appears promising. Propacetamol is a N,N-diethylester of acetaminophen, a non-opioid analgesic used to treat mild pain conditions. In vivo, it is hydrolysed into N,N-diethylglycine (DEG) and acetaminophen. DEG has structural similarities to known alternative GlyT1 substrates. In this study, we analyzed possible effects of propacetamol, or its metabolite N,N-diethylglycine (DEG), on GlyRs or GlyTs function by using a two-electrode voltage clamp approach in Xenopus laevis oocytes. Our data demonstrate that, although propacetamol or acetaminophen had no effect on the function of the analysed glycine-responsive proteins, the propacetamol metabolite DEG acted as a low-affine substrate for both GlyT1 (EC50 > 7.6 mM) and GlyT2 (EC50 > 5.2 mM). It also acted as a mild positive allosteric modulator of GlyRα1 function at intermediate concentrations. Taken together, our data show that DEG influences both glycine transporter and receptor function, and therefore could facilitate glycinergic neurotransmission in a multimodal manner.

Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics

“…Glycine is a small nonessential amino acid not containing a chiral center functioning as both an inhibitory and excitatory neurotransmitter depending on the binding site in CNS. The inhibitory action is mediated by a ligand-gated ion channel known as GlyR, pharmacologically characterized by strychnine sensitivity, and mainly localized in the spinal cord where it plays an important role in nociceptive transmission [ 319 , 320 , 321 , 322 , 323 , 324 , 325 ]. On the other hand, the excitatory effect depends on the glycine B site, defined as a modulatory strychnine-insensitive site of the GluN1 subunit at the NMDAR ion channel.…”

Glycine Transporters and Receptors as Targets for Analgesics

“…Regarding the pharmacology of GlyTs, Barsch and colleagues [4] explored the pharmacology of propacetamol, a non-opioid analgesic used in post-operative care and to treat mild pain conditions. Propacetamol is hydrolysed in vivo into N,N-diethylglycine (DEG) and acetaminophen.…”