Nicorandil reduces morphine withdrawal symptoms, potentiates morphine antinociception, and ameliorates liver fibrosis in rats

Abstract

Aims: Chronic liver disease (CLD) is a serious medical condition affecting patients globally and pain management poses a unique challenge. ATP-sensitive potassium channels (K_ATP) are expressed in nociceptive neurons and hepatic cells. We tested the hypothesis whether morphine and nicorandil, K_ATP channel opener, alone and in combination possess hepatoprotective, antinociceptive effect and alter morphine physical dependence.

Main methods: Intraperitoneal injection (i.p.) of carbon tetrachloride (CCl₄) induced liver fibrosis in male Wistar rats. Nicorandil (15 mg/kg/day) was administered per os for two weeks. Morphine (3.8, 5, 10 mg/kg, i.p.) was administered prior to antinociception testing in tail flick and formalin tests. Morphine physical dependence following naloxone injection, fibrotic, oxidative stress markers, and liver histopathology were assessed.

Key findings: Morphine alone, produced insignificant changes of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), hepatic hydroxyproline (Hyp), malondialdehyde (MDA), and superoxide dismutase (SOD) levels and exerted significant antinociception in the pain models. Nicorandil alone protected against liver damage (decreased serum ALT, AST, HA, hepatic Hyp, MDA, increased SOD levels, improved fibrosis scores). Nicorandil/morphine combination produced remarkable hepatoprotection and persistent analgesia compared to morphine alone as evidenced by reduced (EC50) of morphine. Nicorandil augmented morphine analgesia and markedly decreased withdrawal signs in morphine-dependent rats.

Significance: The data showed for the first time, the hepatoprotection and augmented antinociception mediated by nicorandil/morphine combination in liver fibrosis via antioxidant and antifibrotic mechanisms. Nicorandil ameliorated withdrawal signs in morphine dependence in CLD. Thus, combining nicorandil/morphine provides a novel treatment strategy to ameliorate hepatic injury, potentiate antinociception and overcome morphine-induced physical dependence in liver fibrosis.

Keywords: Antinociception; Hepatoprotection; Liver injury; Opioids; Oxidative stress; Physical dependence.