Vincristine is the drug of choice for Hodgkin’s lymphoma, acute lymphoblastic leukemia, and non-Hodgkin lymphoma. Despite its significant anticancer effects, it causes dose-dependent neuropathy, leading to compulsive dose reduction. The suggested mechanisms of vincristine-induced peripheral neuropathic pain (VIPNP) are complex and include an increased release of tumor necrosis factor α centrally and peripherally, increased 5-hydroxytryptamine (5-HT2A) receptors on dorsal horn and dorsal root ganglion (DRG) neurons, increased reactive oxygen species (ROS) and an altered intrinsic antioxidant mechanism. The available drugs used for VIPNP include antidepressants, antiepileptics and opiates, which have a range of safety, efficacy, and tolerability issues prompting a search for new therapies.6,7,8-Trimethoxycoumarin (678TMC) is a natural coumarin found in Cryptocarya bracteolate, Sapium discolor, Platypodium elegans, Sapium sebiferum, Zanthoxylum lemairie and Zanthoxylum rugosum, and it possesses anti-inflammatory, antioxidant, and carbonic anhydrase-I-inhibitory effects. This study was designed to investigate the possible analgesic and antiallodynic effects of 678TMC in a murine model of VIPNP. Vincristine was administered to groups of BALB/c male mice (0.1 mg/kg intraperitoneally) once daily for 14 days to induce VIPNP. The writhing test was performed after injection of acetic acid intraperitoneally. Thermal hyperalgesia and static mechanical allodynia were tested using tail immersion and Von Frey pressure methods. Cold and dynamic allodynia were quantified using acetone and cotton buds. 678TMC significantly repressed the number of abdominal constrictions and clearly reversed VIPNP thermal hyperalgesia, mechanical static allodynia, mechanical dynamic allodynia, and cold allodynia. Hyperalgesia and allodynia were reversed by pre-treatment with Ondansetron and Naloxone. Vincristine induced Alterations in Vitamin C and most of the neurotransmitters concentrations in the striatum, frontal cortex and hippocampus were reversed by 678TMC. 678TMC reversed the VIPNP increased plasma level of TNF-α. In reversing the alterations in the concentrations of some neurotransmitters in the brain caused by vincristine, 678TMC showed stronger effects than gabapentin. 678TMC attenuates VIPNP by reducing neuroinflammation and targeting the opioidergic and serotonergic systems.

Key Words: Vincristine Induced Peripheral Neuropathic Pain, 6,7,8 Trimethoxycoumarin, 5HT₃ receptors, Opioid receptors, TNF-α, Vitamin C