2. Academic Validation
  3. Chronic morphine induces cyclic adenosine monophosphate formation and hyperpolarization-activated cyclic nucleotide-gated channel expression in the spinal cord of mice

Chronic morphine induces cyclic adenosine monophosphate formation and hyperpolarization-activated cyclic nucleotide-gated channel expression in the spinal cord of mice

  • Neuropharmacology. 2020 Oct 1;176:108222. doi: 10.1016/j.neuropharm.2020.108222.
Lin Yuan 1,  Limin Luo 2,  Xiaqing Ma 2,  Wenying Wang 2,  Kangkang Yu 3,  Haibo Shi 4,  Jian Chen 5,  Dake Chen 6,  Tao Xu 7
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Tongzhou People's Hospital, Nantong, 226300, China.
  • 2 Department of Anesthesiology, Affiliated Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, 200233, China.
  • 3 Department of Pathology, Tongzhou People's Hospital, Nantong, 226300, China.
  • 4 Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, 200233, China.
  • 5 Department of Orthopaedics, Tongzhou People's Hospital, Nantong, 226300, China. Electronic address: tzcj@nttzhospital.com.
  • 6 Department of Oncology, Tongzhou People's Hospital, Nantong, 226300, China. Electronic address: tzcdk@nttzhospital.com.
  • 7 Department of Anesthesiology, Tongzhou People's Hospital, Nantong, 226300, China; Department of Anesthesiology, Affiliated Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, 200233, China. Electronic address: balor@sjtu.edu.cn.
PMID: 32659289 DOI: 10.1016/j.neuropharm.2020.108222
Abstract

Chronic morphine exposure persistently activates Gαi/o protein-coupled receptors and enhances adenylyl cyclase (AC) activity, which can increase cyclic adenosine monophosphate (cAMP) production. Direct binding of cAMP to the cytoplasmic site on hyperpolarization-activated cyclic nucleotide-gated (HCN) channels increases the probability of channel opening. HCN channels play a prominent role in chronic pain the disease that shares some common mechanisms with opioid tolerance. This compensatory AC activation may be responsible for the induction of morphine-induced analgesic tolerance. We investigated spinal cAMP formation and expression of HCN2 in the spinal cord, and observed the effect of AC inhibition on the induction of morphine analgesic tolerance. We found that chronic morphine-induced antinociceptive tolerance increased spinal cAMP formation and the expression of spinal HCN2. Inhibition of spinal AC partially blocked chronic morphine-induced cAMP formation and prevented the induction of morphine-induced analgesic tolerance. Inhibition of HCN2 also showed a partial preventive effect on morphine-induced tolerance, hypothermia tolerance and also the right-shift of the dose-response curve. We conclude that repeated morphine treatment increases AC activity and cAMP formation, and also spinal HCN2 expression, blockade of AC or HCN2 can prevent the development of morphine-induced analgesic tolerance.

Keywords

Adenylyl cyclase; Cyclic adenosine monophosphate; HCN; Hyperpolarization-activated cyclic nucleotide-gated channel; Morphine; Tolerance; cAMP.

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