Background & Aims
Resolvin D1 (RvD1) is a lipid signaling molecule synthesized from ?-3 polyunsaturated fatty acids. RvD1 produces peripheral pro-resolving effects (1) and antinociception by acting on peripheral and central neurons (2). RvD1 could be considered a potential antinociceptive substance for the treatment of pain to reduce opioid usage. More than 80% of patients with bone cancer experience excruciating cancer-induced bone pain (CIBP) (3). Using a mouse model of CIBP we demonstrated that bone cancer sensitizes peripheral nociceptors, spinal neurons, and neurons of the Rostral Ventromedial Medulla (RVM), a brainstem structure that is involved in descending modulation of pain (4, 5). However, the role of the RVM in modulating CIBP is still unclear. This investigation aims to evaluate: I) the anti-nociceptive effect of systemic RvD1 during CIBP and II) its effect on response properties of descending anti- and pro-nociceptive neurons in the RVM.
Methods
Bone cancer model: CIBP was produced by injection of fibrosarcoma cells into the calcaneus bone of C3H mice of both sexes. Experiments were performed on 14-19 days.
Behavior studies: Paw withdrawal frequency [PWF (%)] was evaluated by 10 applications of von Frey monofilament (0.4 g) applied to the plantar surface of the paw. Paw withdrawal threshold [PWT (g)] was determined by the Up-Down method (6). Heat withdrawal latency [HWL (s)] was determined in response to radiant heat applied to the plantar surface. The effect of RvD1 (0.001-10 µg/kg) given intravenously (i.v.) was determined using PWF. Effects of RvD1 3 µg/kg in naïve and tumor-bearing mice were determined by PWT and HWL.
Electrophysiological studies of the RVM: Single unit recordings of ON (pro-) and OFF (anti-nociceptive) cell responses to mechanical and thermal stimulation were determined before and at 30 and 60 minutes after i.v. administration of RvD1 3 µg/kg in cancer and naïve mice.
Results
RvD1 inhibited CIBP, evaluated by PWF and expressed as an area under the curve with ED50 = 0.0015 µg/kg in both sexes. In cancer mice, RvD1 3 µg/kg reduced mechanical and thermal hyperalgesia, indicated by an increase in PWT and HWL. No effects were found in naïve mice. Electrophysiological studies revealed that in cancer mice, ON cells had increased responses and OFF cells had a stronger reduction of activity evoked by heat, cold, and mechanical stimulations of the cancer paw compared to naïve mice. Responses of ON cells from the contralateral to cancer paw were similar to naïve mice, but inhibition of OFF cells was significantly stronger than in naïve mice. RvD1 (i.v. 3 µg/kg) reduced the evoked activity of ON cells and the inhibition of OFF cells in cancer mice to those in naïve mice. RvD1 or vehicle (0.3% ethanol in saline) did no alter responses of ON and OFF cells in naïve mice.
Conclusions
1). Resolvin D1 produces potent antinociception in a mouse model of CIBP independent of sex.
2). CIBP induces descending pronociception from the RVM by increasing evoked activity of ON cells facilitation and decreasing inhibitory responses of OFF cells.
3). Resolvin D1 decreases activity of ON cells and increases activity of OFF cells to reduce hyperalgesia in mice with CIBP, but does not alter RVM activity in naïve mice.
Source of Financial Support: CA263777 and CA241627.
References
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3.R. Zajaczkowska, M. Kocot-Kepska, W. Leppert, J. Wordliczek, Bone Pain in Cancer Patients: Mechanisms and Current Treatment. Int J Mol Sci 20, (2019).
4.D. M. Cain et al., Functional interactions between tumor and peripheral nerve: changes in excitability and morphology of primary afferent fibers in a murine model of cancer pain. The Journal of neuroscience : the official journal of the Society for Neuroscience 21, 9367-9376 (2001).
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Presenting Author
Sergey G. Khasabov
Poster Authors
Sergey Khasabov
MD, PhD
University of Minnesota
Lead Author
Alyssa M. Flippen B.S.
University of Minnesota
Lead Author
Xijing Zhang M.D.
University of Minnesota
Lead Author
Lauren Loppnow
University of Minnesota
Lead Author
Iryna Khasabova
University of Minnesota
Lead Author
Donald A. Simone Ph.D.
UMN
Lead Author
Topics
- Treatment/Management: Pharmacology: Non-opioid