Background & Aims

Changes in the central nervous system may underlie the transition to chronic pain, but our understanding of these changes is insufficient to predict and prevent the transition to chronic pain. A small population of neurons referred to as A11 project ipsilaterally to all levels of the spinal cord, where they release dopamine. A faciliatory role has been suggested for spinal dopamine in animals vulnerable to chronic pain from a prior inflammatory insult, however this system had not previously been explored in a noninflammatory model of chronic pain. Additionally, very little is known about the activity and properties of A11 neurons. We hypothesize that A11 neurons become active following peripheral insult to facilitate the transition to chronic pain via D1-like receptor mediated phosphorylation of NMDA receptors. We aim to determine the role of D1-like receptors in the transition to chronic pain and characterize the activity of A11 neurons in animals with and without chronic pain.

Methods

Adult male and female C57BL6/J mice were used in this study. Chronic, non-inflammatory, musculoskeletal pain was induced by two intramuscular injections (pH 4.0) five days apart in the left gastrocnemius muscle. The second injection initiates the transition to chronic pain. We performed pharmacological manipulation prior to the initiation of chronic pain to test the role of spinal D1-like receptor activity in the transition to chronic pain. To assess pain, muscle withdrawal thresholds and paw sensitivity were evaluated at baseline and after initiation of chronic pain. Additionally, we collected tissue from the brain and spinal cord of animals with and without chronic pain to evaluate A11 dopamine neuron activity, D1-like receptors, and NMDA receptors in the context of chronic pain.

Results

A single application of a D1-like receptor antagonist prior to the initiation of chronic pain delayed the onset of hyperalgesia in male mice. Compared to control, mice that received the antagonist displayed an increased muscle withdrawal threshold for at least 24 hours, as well as decreased paw sensitivity for 1 week following the induction of chronic pain. Interestingly, female mice did not show any effect of D1-like receptor antagonism as measured by muscle withdrawal threshold or paw sensitivity. Because these data implicate D1-like receptors in the development of chronic pain, we measured expression of mRNA for D1-like receptors in the spinal cord of mice with chronic pain. We similarly measured expression of mRNA of NMDA receptors, which we have previously implicated in the transition to chronic pain. We found no increase in D1-like receptor or NMDA receptor mRNA following the transition to chronic pain.

Conclusions

We found that in our model of chronic, non-inflammatory, musculoskeletal pain, D1-like receptor activity is necessary for the transition to chronic pain in male but not female mice. The observed effects of D1-like receptor antagonism far outlast how long the drug is present in the system, suggesting mechanisms downstream of D1-like receptors are involved in the transition to chronic pain. D1-like receptor mRNA expression is not elevated in the spinal cord following the transition to chronic pain in males or females, nor is NMDA receptor mRNA expression. This supports our hypothesis that D1-like receptors facilitate the transition to chronic pain in males via signaling pathways downstream of D1-like receptor activation. Additional experiments will characterize the activity and properties of A11 dopamine neurons, the source of spinal dopamine. Future directions will explore if spinal D1-like receptor activation mediates phosphorylation of NMDA receptors.

References

1) Fleetwood-Walker, S. M., Hope, P. J., & Mitchell, R. (1988). Antinociceptive actions of descending dopaminergic tracts on cat and rat dorsal horn somatosensory neurones. The Journal of Physiology, 399, 335–348. https://doi.org/10.1113/jphysiol.1988.sp017084
2) Kim, J.-Y. V., Tillu, D. V., Quinn, T. L., Mejia, G. L., Shy, A., Asiedu, M. N. K., Murad, E., Schumann, A. P., Totsch, S. K., Sorge, R. E., Mantyh, P. W., Dussor, G., & Price, T. J. (2015). Spinal dopaminergic projections control the transition to pathological pain plasticity via a D1/D5-mediated mechanism. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 35(16), 6307–6317. https://doi.org/10.1523/JNEUROSCI.3481-14.2015
3) Sluka, K. A., Kalra, A., & Moore, S. A. (2001). Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia. Muscle & Nerve, 24(1), 37–46. https://doi.org/10.1002/1097-4598(200101)24:1<37::aid-mus4>3.0.co;2-8
4) Skyba, D. A., King, E. W., & Sluka, K. A. (2002). Effects of NMDA and non-NMDA ionotropic glutamate receptor antagonists on the development and maintenance of hyperalgesia induced by repeated intramuscular injection of acidic saline. Pain, 98(1–2), 69–78. https://doi.org/10.1016/s0304-3959(01)00471-7

Presenting Author

Angela Smith

Poster Authors

Angela Smith

BSc

University of Iowa

Lead Author

E-mail

Kazuhiro Hayashi

Kyoto University, Kyoto, Japan

Lead Author

E-mail

Adam Janowski

DPT

Lead Author

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Ashley Plumb

Lead Author

E-mail

Stephanie Gantz

Lead Author

E-mail

Kathleen Sluka

PT

University of Iowa, Carver College of Medicine

Lead Author

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Topics

  • Mechanisms: Biological-Systems (Physiology/Anatomy)