Activation of P2X7 receptors in the midbrain periaqueductal gray of rats facilitates morphine tolerance

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2015-08, Vol.135, p.145-153
• Main Authors: Xiao, Zhi, Li, You-Yan, Sun, Meng-Jie
• Format: Article
• Language: English
• Subjects: Acetamides - pharmacology; Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - pharmacology; Animals; Drug Tolerance; Male; Mesencephalon - drug effects; Midbrain periaqueductal gray; Morphine; Morphine - pharmacology; Narcotics - pharmacology; Oligodeoxyribonucleotides, Antisense - pharmacology; P2X7 receptor; Pain Measurement - drug effects; Pain Threshold - drug effects; Periaqueductal Gray - drug effects; Purinergic P2X Receptor Agonists - pharmacology; Purinergic P2X Receptor Antagonists - pharmacology; Quinolines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2X7 - drug effects; Substance Withdrawal Syndrome - psychology; Tolerance
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2015.06.002

Opiates such as morphine exhibit analgesic effect in various pain models, but repeated and chronic morphine administration may develop resistance to antinociception. The purinergic signaling system is involved in the mechanisms of pain modulation and morphine tolerance. This study aimed to determine whether the P2X7 receptor in the ventrolateral midbrain periaqueductal gray (vlPAG) is involved in morphine tolerance. Development of tolerance to the antinociceptive effect of morphine was induced in normal adult male Sprague–Dawley (SD) rats through subcutaneous injection of morphine (10mg/kg). The analgesic effect of morphine (5mg/kg, i.p.) was assessed by measuring mechanical withdrawal thresholds (MWTs) in rats with an electronic von Frey anesthesiometer. The expression levels and distribution of the P2X7 receptor in the vlPAG was evaluated through Western blot analysis and immunohistochemistry. The acute effects of intra-vlPAG injection of the selective P2X7 receptor agonist Bz-ATP, the selective P2X7 receptor antagonist A-740003, or antisense oligodeoxynucleotide (AS ODN) targeting the P2X7 receptor on morphine-treated rats were also observed. Results demonstrated that repeated morphine administration decreased the mechanical pain thresholds. By contrast, the expression of the P2X7 receptor protein was up-regulated in the vlPAG in morphine tolerant rats. The percent changes in MWT were markedly but only transiently attenuated by intra-vlPAG injection of Bz-ATP (9nmol/0.3μL) but elevated by A-740003 at doses of 10 and 100nmol/0.3μL. AS ODN (15nmol/0.3μL) against the P2X7 receptor reduced the development of chronic morphine tolerance in rats. These results suggest that the development of antinociceptive tolerance to morphine is partially mediated by activating the vlPAG P2X7 receptors. The present data also suggest that the P2X7 receptors may be a therapeutic target for improving the analgesic effect of morphine in treatments of pain when morphine tolerance occurs. •The expression of the P2X7 receptor in vlPAG is upregulated in morphine tolerance.•Bz-ATP temporarily potentiated the morphine tolerance in rats.•A-740003 transiently reduces the morphine tolerance in rats.•P2X7 receptor antisense ODN reduces the development of morphine tolerance.