Mechanism of Spinal Analgesic Effect of Resolvin D1
Resolvin D1 (RvD1), a derivative of ω-3 polyunsaturated fatty acids, is a specialized pro-resolving mediator. It produces resolving effects by terminating inflammatory responses and promoting tissue healing. While it has been found that exogenous RvD1
produces anti-hyperalgesia in a model of bone cancer pain, its primary mechanism of action is not fully understood. In this study, we investigated RvD1’s effects on a key promoter of inflammation, Hypoxia-Inducible Factor-1α (HIF-1α), as there is an up-regulation of this transcription factor in bone cancer that is associated with higher sensitization in the spinal cord. We increased the stability of HIF-1α by 5 daily intrathecal injections of 4,4α-dihydro-4-oxo-1,10-phenanthroline-3-carboxylic acid (1,4-DPCA) in male and female CH3 mice. This treatment led to an increase in HIF-1α expression and hyperalgesia in both hind paws. The development of hyperalgesia was determined by paw withdrawal thresholds using the von Frey up-down method and automated paw luminance ratios from Blackbox Palmreader software. Intrathecal injection of RvD1 (0.33 and 1 ng in 5 μl) significantly reduced HIF-1α-dependent
hyperalgesia, while no substantial effects were observed in the vehicle-treated group (5 μl of 1% ethanol). Because we found that RvD1 produced partial anti-hyperalgesia through the inhibition of HIF-1α-dependent hyperalgesia, our findings suggest that RvD1
could be a potential treatment for cancer pain.