(249) - Role of nerve growth factor/tyrosine kinase receptor a signaling in the plasma of morphine tolerant rat

Abstract

Morphine is extensively used as an analgesic in pain management. However, repeated administration of morphine produces tolerance. In the central nervous system, nerve growth factor (NGF) and its receptor, tyrosine kinase receptor A (TrkA), are involved in pain, analgesia, and tolerance mechanisms. Additionally, multiple clinical and animal studies have shown changes in circulating NGF in various neurological disorders. In the present study, we investigated the effects of chronic morphine treatment on the NGF-TrkA pathway in morphine-induced tolerant rats. Animals were treated with morphine with or without concomitant administration of the tyrosine kinase receptor A antagonist K252a. The morphine (10 mg/kg; subcutaneous) or K252a (80 µg/kg; intraperitoneal) treatment regime was 2x/day for five days. On the sixth day, a single injection of morphine/K252a was administered. The development of tolerance was assessed by changes in paw withdrawal latency (PWL) to noxious thermal stimuli (Thermal test). The change in plasma NGF levels was measured by ELISA. PWL progressively decreased in rats that received repeated morphine treatments indicating development of antinociceptive and morphine tolerance. Morphine tolerant rats showed two fold increases in the plasma NGF level compared to saline-treated control rats. Co-administration of morphine and K252a increased PWL and also reduced the plasma NGF levels. These initial findings suggest that plasma NGF-TrkA signaling contributes to the development of opioid tolerance. This research was supported by Congressionally Directed Medical Research Programs- Applied Pain Research grant (MR157005C).