Disruption of 5-HT2A-PDZ protein interaction differently affects the analgesic efficacy of SSRI, SNRI and TCA in the treatment of traumatic neuropathic pain in rats

Neuropharmacology. 2017 Oct:125:308-318. doi: 10.1016/j.neuropharm.2017.07.034. Epub 2017 Aug 2.

Abstract

Antidepressants remain one of the first line treatments prescribed to neuropathic pain patients despite their limited efficacy and/or their numerous side effects. More and more, pharmacotherapy for neuropathic pain has evolved towards the use of therapeutic combinations. The goal of the present study was to assess the efficacy of the combination of antidepressants - selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors-with a peptide (TAT-2ASCV) able to disrupt the interaction between serotonin type 2A (5-HT2A) receptors and associated PDZ proteins. Mechanical hypersensitivity was assessed in sciatic nerve ligation-induced neuropathic pain in rats using paw pressure test after acute treatment with TAT-2ASCV alone or in combination with repeated treatment with fluoxetine or duloxetine or clomipramine. First, we validated the anti-hyperalgesic effect of TAT-2ASCV on mechanical hypersensitivity at the dose of 100 ng/rat (single i.t. injection). Second, using selective receptor antagonists, we found that the effect of TAT-2ASCV on mechanical hypersensitivity involves 5-HT2A as well as GABAA receptors. Finally, we showed that the association of TAT-2ASCV (100 ng, single i.t. injection) with fluoxetine (10 mg/kg, five i.p. injections) reveals its anti-hyperalgesic effect, while the association with duloxetine (1 mg/kg, five i.p. injections) or clomipramine (2.5 mg/kg, five i.p. injections) is only additive. Those results further accentuate the interest to develop small molecules acting like TAT-2ASCV in order to treat neuropathic pain as a monotherapy or in combination with antidepressants.

Keywords: 5-HT(2A) receptors; Alpha-methyl-5-hydroxy-tryptamine maleate (PubChem CID: 2107); Bicuculline (PubChem CID: 10237); Clomipramine; Clomipramine hydrochloride (PubChem CID: 68539); Duloxetine; Duloxetine hydrochloride (PubChem CID: 60834); Fluoxetine; Fluoxetine hydrochloride (PubChem CID: 62857); GABA; M100907 (PubChem CID: 60858); Mechanical hyperalgesia; Neuropathic pain; PDZ proteins.

MeSH terms

  • Analgesics, Non-Narcotic / pharmacology*
  • Animals
  • Clomipramine / pharmacology
  • Disease Models, Animal
  • Duloxetine Hydrochloride / pharmacology
  • Fluoxetine / pharmacology
  • GABA-A Receptor Agonists / pharmacology
  • Hyperalgesia / drug therapy
  • Hyperalgesia / metabolism
  • Male
  • Neuralgia / drug therapy*
  • Neuralgia / metabolism
  • PDZ Domains*
  • Peripheral Nervous System Diseases / drug therapy
  • Peripheral Nervous System Diseases / metabolism
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Receptors, GABA-A / metabolism
  • Sciatic Nerve
  • Selective Serotonin Reuptake Inhibitors / pharmacology*
  • Serotonin 5-HT2 Receptor Agonists / pharmacology
  • Serotonin and Noradrenaline Reuptake Inhibitors / pharmacology*
  • Touch

Substances

  • Analgesics, Non-Narcotic
  • GABA-A Receptor Agonists
  • Receptor, Serotonin, 5-HT2A
  • Receptors, GABA-A
  • Serotonin 5-HT2 Receptor Agonists
  • Serotonin Uptake Inhibitors
  • Serotonin and Noradrenaline Reuptake Inhibitors
  • Fluoxetine
  • Duloxetine Hydrochloride
  • Clomipramine