Phα1β, a dual blocker of TRPA1 and Cav2.2, as an adjuvant drug in opioid therapy for postoperative pain

• Published in: Toxicon (Oxford) 2020-12, Vol.188, p.80-88
• Main Authors: Tonello, Raquel, Trevisan, Gabriela, Luckemeyer, Débora, Castro-Junior, Celio J., Gomez, Marcus Vinicius, Ferreira, Juliano
• Format: Article
• Language: English
• Subjects: Opioid-induced hyperalgesia; Postoperative pain; Tolerance; TRPA1; Voltage-gated calcium channels; Withdrawal syndrome
• ISSN: 0041-0101; 1879-3150
• DOI: 10.1016/j.toxicon.2020.10.007

Opioids are the “gold standard” treatment for postoperative pain, but these drugs also have limiting adverse effects. Thus, adjuvant drugs might be useful in opioid therapy for postoperative pain. The aim of the present study was to evaluate the effect of Phα1β, a dual blocker of Cav2 and TRPA1 channels, on antinociceptive and adverse actions of morphine in a model of postoperative pain. Phα1β (100–300 pmol/site) or morphine (3–10 mg/kg), alone, largely reduced postoperative nociception. However, Phα1β (100 pmol/site) or morphine (10 mg/kg) also produced motor impairment. Lower doses of Phα1β (30 pmol/site) or morphine (1 mg/kg), that did not have an effect alone, showed antinociceptive effect when concomitantly administrated. Moreover, co-administration of Phα1β (30 pmol/site) with morphine (1 or 10 mg/kg) was unable to cause motor impairment. Preoperative repeated treatment with morphine increased the expression of Cav2 and TRPA1 channels in spinal cord, and caused tolerance and withdrawal syndrome, which were reversed with a single injection of Phα1β (30 pmol/site). When injected postoperatively, escalating doses of morphine worsened postoperative hyperalgesia, induced tolerance, and withdrawal syndrome. Similarly, Phα1β (30 pmol/site) reversed these adverse effects. Single or repeated morphine caused constipation, which was not altered by Phα1β. Thus, a low dose of Phα1β potentiated the analgesia, and reversed some adverse effects of morphine on operated mice, indicating the potential use of this agent as an adjuvant drug in opioid therapy for postoperative pain. •Phα1β produces an antinociceptive effect on postoperative pain.•Phα1β potentiates the analgesic effects of a single dose of morphine in operated mice.•Preoperative use of morphine induces tolerance and withdraw syndrome.•Postoperative morphine produces hyperalgesia, tolerance and withdrawal syndrome.•Phα1β reverses tolerance and adverse effects induced by morphine on operated mice.