Exploring the analgesic potential of isorhamnetin: insights from formalin-induced pain and diabetic neuropathy models.

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Isorhamnetin, a naturally occurring flavonoid compound, holds paramount importance as a primary constituent within several medicinal plants, exhibiting profound pharmacological significance. The aim of this study is to investigate the pain-relieving attributes of isorhamnetin in murine models through both formalin-induced pain and diabetic neuropathy scenarios. To achieve our objective, isorhamnetin was orally administered to mice at varying dosage levels (10 to 100 mg/kg). Pain-related behaviors were assessed using the formalin test during its secondary phase. Additionally, the potential pain-alleviating effect of isorhamnetin was evaluated in a diabetic neuropathy model induced by streptozotocin. Additionally, we carried out advanced interventions using naloxone, which is a well-known antagonist of opioid receptors, yohimbine, which blocks α2-adrenergic receptors, and methysergide, which inhibits serotonergic receptors, during the formalin test. The oral intake of isorhamnetin showed a decrease in behaviors associated with pain that was proportional to the dose observed during the second phase of the formalin test when induced by formalin. In the diabetic neuropathy model, isorhamnetin administration effectively reversed the reduced pain threshold observed. Notably, naloxone, the opioid receptor antagonist, effectively counteracted the pain-relieving effect produced by isorhamnetin in the formalin test, whereas yohimbine and methysergide did not yield similar outcomes. Isorhamnetin also led to a reduction in elevated spinal cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) levels triggered by formalin, with this effect reversed by pre-treatment with naloxone. The compound also suppressed heightened spinal phosphorylated CREB (p-CREB) levels caused by diabetic neuropathy. This research determined that isorhamnetin has notable abilities to relieve pain in models of formalin-induced pain and diabetic neuropathy. The pain-relieving mechanism of isorhamnetin in the formalin-induced pain model seems to be connected to the activation of spinal opioid receptors and the adjustment of CREB protein amounts. This insight improves our knowledge of how isorhamnetin could be used therapeutically to treat pain conditions stemming from formalin-induced pain and diabetic neuropathy.