Experimental malignancy in the rat induces early hypersensitivity indicative of neuritis

Abstract

Cancer pain mechanisms involve multiple factors including the accompanying inflammatory process neural effects. Inflammation along a nerve trunk (neuritis) has been shown to induce hypersensitivity at the innervated target organ. In this experiment the neural effects of MAT B mammary adenocarcinoma cells implanted adjacent to sciatic nerve (MAT group) were compared to those induced by thymus cell extract (THY), saline (SAL) and the potent proinflammatory agent Complete Freund's adjuvant (CFA). Significant pain behavior was detected only in the ipsilateral hindpaw of MAT and CFA rats lasting seven days post-operatively (dpo). On the ninth dpo MAT rats developed significant hyposensitivity to mechanical and electrical stimuli. Interleukin (IL)-6 levels (ELISA) from MAT and CFA exposed nerves were significantly elevated at dpo 2 and remained so in MAT at dpo 8. Indomethacin (1 mg/kg i.p.) abolished the observed pain responses in MAT and CFA rats exposed nerves. Light microscopy of the MAT nerves at the second dpo revealed neural infiltration of immune and malignant cells with mild edema. By the seventh dpo there was nerve damage and at dpo 14 nerve tissue was largely replaced by malignant and immune cells. Electrophysiology of saphenous nerves exposed to MAT, CFA or SAL revealed significantly increased spontaneous activity in MAT and CFA groups. Spike response to hindpaw mechanical stimulation was significantly reduced only in the MAT group (dpo 6–9) suggestive of nerve damage. Inflammatory neuritis is an early expression of malignancy and may play a role in chronic cancer-related pain initiation and additionally may offer diagnostic opportunities.