Dopamine D 1 and D 2 receptors mediate analgesic and hypnotic effects of l-tetrahydropalmatine in a mouse neuropathic pain model

Psychopharmacology (Berl). 2019 Nov;236(11):3169-3182. doi: 10.1007/s00213-019-05275-3. Epub 2019 Jun 6.

Abstract

Rationale: Levo-tetrahydropalmatine (l-THP), an active ingredient of Corydalis yanhusuo, has been reported to be a partial agonist for dopamine D1 receptors (D1R) and an antagonist for D2R. Although it has been safely used clinically in China for decades as an analgesic with sedative/hypnotic properties, there are few studies that address the mechanisms by which l-THP exerts its beneficial effects in chronic pain-induced sleep disturbance.

Objectives: To investigate the effects and mechanisms of l-THP on sleep disturbance in a neuropathic pain-like condition.

Methods: A mouse model of chronic neuropathic pain induced by partial sciatic nerve ligation (PSNL) was employed. The antinociceptive and hypnotic effects of l-THP were evaluated by measurement of mechanical allodynia, thermal hyperalgesia, and electroencephalogram (EEG) recordings in PSNL mice. Pharmacological approaches and c-Fos expression were used to clarify the mechanisms of l-THP.

Results: Intraperitoneal injection of l-THP at 5 and 10 mg/kg not only significantly increased the mechanical threshold by 134.4% and 174.8%, and prolonged the thermal latency by 49.4% and 69.2%, but also increased non-rapid eye movement sleep by 17.5% and 29.6%, and decreased sleep fragmentation in PSNL mice, compared with the vehicle control. Moreover, the antinociceptive effect of l-THP was prevented by D1R antagonist SCH23390 or D2R agonist quinpirole; meanwhile, the hypnotic effect of l-THP was blocked by quinpirole rather than by SCH23390. Immunohistochemistry demonstrated that l-THP inhibited c-Fos overexpression induced by PSNL in the cingulate cortex and the periaqueductal gray.

Conclusions: These findings indicated that l-THP exerted analgesic effects by agonism D1R and antagonism D2R, and the antagonism of D2R mediated the hypnotic effect of l-THP in PSNL mice.

Keywords: Dopamine receptor; Levo-tetrahydropalmatine; Neuropathic pain; Sleep disturbance; c-Fos.

MeSH terms

  • Analgesics, Non-Narcotic / pharmacology
  • Analgesics, Non-Narcotic / therapeutic use*
  • Animals
  • Berberine Alkaloids / pharmacology
  • Berberine Alkaloids / therapeutic use*
  • Disease Models, Animal
  • Dopamine D2 Receptor Antagonists / pharmacology
  • Dopamine D2 Receptor Antagonists / therapeutic use
  • Electroencephalography / drug effects
  • Hypnotics and Sedatives / pharmacology
  • Hypnotics and Sedatives / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuralgia / drug therapy*
  • Neuralgia / physiopathology
  • Receptors, Dopamine D1 / agonists
  • Receptors, Dopamine D1 / physiology*
  • Receptors, Dopamine D2 / physiology*

Substances

  • Analgesics, Non-Narcotic
  • Berberine Alkaloids
  • Dopamine D2 Receptor Antagonists
  • Hypnotics and Sedatives
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • tetrahydropalmatine