Role of Spinal Cord α2-Adrenoreceptors in Noradrenergic Inhibition of Nociceptive Transmission During Chemotherapy-Induced Peripheral Neuropathy

José Tiago Costa-Pereira; Joana Ribeiro; Isabel Martins; Isaura Tavares

doi:10.3389/fnins.2019.01413

Role of Spinal Cord α₂-Adrenoreceptors in Noradrenergic Inhibition of Nociceptive Transmission During Chemotherapy-Induced Peripheral Neuropathy

Front Neurosci. 2020 Jan 15:13:1413. doi: 10.3389/fnins.2019.01413. eCollection 2019.

Authors

José Tiago Costa-Pereira^{1

2

3}, Joana Ribeiro^{1

2

3}, Isabel Martins^{1

2

3}, Isaura Tavares^{1

2

3}

Affiliations

¹ Unit of Experimental Biology, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal.
² Institute of Molecular and Cell Biology, University of Porto, Porto, Portugal.
³ I3S-Institute for Investigation and Innovation in Health, University of Porto, Porto, Portugal.

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a problem during cancer treatment and for cancer survivors but the central mechanisms underlying CIPN remain understudied. This study aims to determine if CIPN is associated with alterations of noradrenergic modulation of nociceptive transmission at the spinal cord. CIPN was induced in male Wistar rats by paclitaxel injections. One month after CIPN induction, the behavioral effects of the administration of reboxetine (noradrenaline reuptake inhibitor), clonidine (agonist of α₂-adrenoreceptors; α₂ _-AR) and atipamezole (antagonist of α₂ _-AR) were evaluated using the von Frey and cold plate tests. Furthermore, we measured the expression of the noradrenaline biosynthetic enzyme dopamine-β-hydroxylase (DBH) and of α₂ _-AR in the spinal dorsal horn. Reboxetine and clonidine reversed the behavioral signs of CIPN whereas the opposite occurred with atipamezole. In the 3 pharmacological approaches, a higher effect was detected in mechanical allodynia, the pain modality which is under descending noradrenergic control. DBH expression was increased at the spinal dorsal horn of paclitaxel-injected animals. The enhanced noradrenergic inhibition during CIPN may represent an adaptation of the descending noradrenergic pain control system to the increased arrival of peripheral nociceptive input. A potentiation of the α₂ _-AR mediated antinociception at the spinal cord may represent a therapeutic opportunity to face CIPN.

Keywords: antidepressants; cancer treatment; chemotherapy side-effects; descending pain modulation; paclitaxel; pain.