Antinociceptive effects of sinomenine combined with ligustrazine or paracetamol in animal models of incisional and inflammatory pain

The management of post-operative and inflammatory pain has been a pressing challenge in clinical settings. The present strategy involving opioid treatments is not satisfactory, which often associated with tolerance and addiction. Sinomenine (SN) is a morphinan derived alkaloid with remarkable analgesic properties in various kinds of pain models. The aim of the current study is to evaluate if SN can be used to enhance the effect of ligustrazine hydrochloride (LGZ) or paracetamol (PCM) in animal models of post-operative and inflammatory pain. And if therapeutic efficacies can be correlated to pharmacokinetics change due to drug combinations. Pharmacological studies were performed in rat model of incisional pain, or mouse model of carrageenan induced inflammatory pain, 24 hours after incision or carrageenan injection. Pharmacokenetic studies were performed using a sensitive HPLC-QQQ-MS method to quantify SN, LGZ and PCM levels in blood and extracellular fluids of brain. We found that SN and LGZ or SN and PCM produced marked synergistic analgesic effects. However, such synergy was subjected to pain modalities, and drug’s effects were differed in incisional and inflammatory pain. The pharmacological discoveries could be partially explained by pharmacokinetic alterations in SN combinations. Though further clinical evaluation is needed, our findings advocate the potential usages of SN with LGZ or SN with PCM respectively for post-operative pain or acute inflammatory pain as opioid-substitutional analgesics. This study also provided insights into the drug induced neuroimmune interactions reflecting the perplexing physiology of the nociceptive system.