2. Academic Validation
  3. Sex-dependent antiallodynic effect of α2 adrenergic receptor agonist tizanidine in rats with experimental neuropathic pain

Sex-dependent antiallodynic effect of α2 adrenergic receptor agonist tizanidine in rats with experimental neuropathic pain

  • Eur J Pharmacol. 2022 Apr 5:920:174855. doi: 10.1016/j.ejphar.2022.174855.
Erick Josué Rodríguez-Palma 1,  Dania Guadalupe Castelo-Flores 2,  Nadia Lizeth Caram-Salas 3,  Ana Belen Salinas-Abarca 1,  David Centurión 4,  Yarim Elideth De la Luz-Cuellar 1,  Vinicio Granados-Soto 5
Affiliations

Affiliations

  • 1 Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Cinvestav, South Campus. Mexico City, Mexico.
  • 2 Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Cinvestav, South Campus. Mexico City, Mexico; Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Sinaloa, Mexico.
  • 3 Cátedra CONACYT-CICESE, Centro de Investigación Científica y de Educación Superior de Ensenada, Baja California, Mexico.
  • 4 Departamento de Farmacobiología, Cinvestav, South Campus. Mexico City, Mexico.
  • 5 Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Cinvestav, South Campus. Mexico City, Mexico. Electronic address: vgranados@cinvestav.mx.
PMID: 35227682 DOI: 10.1016/j.ejphar.2022.174855
Abstract

The purpose of this study was to investigate the mechanism of antiallodynic effect of tizanidine in neuropathic rats. Spinal nerve ligation reduced withdrawal threshold which was interpreted as tactile allodynia. Increasing doses of tizanidine induced a dose-dependent antiallodynic effect in nerve injured rats. Tizanidine was more effective in female than male neuropathic rats. This drug induced a lower antiallodynic effect in ovariectomized, compared with non-ovariectomized, neuropathic rats, while systemic reconstitution of estradiol (E2) levels in ovariectomized neuropathic females fully restored the antiallodynic effect of tizanidine. Naloxone reduced the antiallodynic effect of tizanidine in male but not in female neuropathic rats. Ovariectomy restored the antagonizing effect of naloxone in the antiallodynic effect of tizanidine, whereas treatment with E2 abolished the effect of naloxone on tizanidine activity. Rauwolscine (α2 antagonist) and imiloxan (α2B antagonist) completely abated tizanidine-induced antiallodynic effect in female neuropathic rats. In contrast, BRL-44408 (α2A antagonist) partially decreased the effect of tizanidine while JP-1302 (α2C antagonist) was ineffective. Rauwolscine, imiloxan and BRL-44408 decreased withdrawal threshold in naïve female rats. Rauwolscine did not modify withdrawal threshold in naïve male rats. AGN192403 (I1 antagonist), BU224 (I2 antagonist), prazosin (α1 antagonist) and methiothepin (5-HT antagonist) did not modify tizanidine-induced antiallodynia in neuropathic females and males. These data indicate that tizanidine exhibits a sex-dependent antiallodynic effect in neuropathy. Data also suggest that activation of adrenergic α2B and α2A and opioid receptors participate in the antiallodynic effect of tizanidine in female and male, respectively, neuropathic rats.

Keywords

Adrenergic receptors; Allodynia; Neuropathic pain; Sex-dependent; Tizanidine.

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