Background & Aims

Depression is often co-morbid with chronic pain [1]. In rodents, chronic pain decreases motivation, one of the many symptoms of depression [2]. In this study, we modeled motivational deficits using an experimental device under a progressive ratio of schedule task [2] and sought to investigate mechanisms underlying this phenomenon. In chronic pain states, dopaminergic signaling is impaired in the nucleus accumbens (NAcc), a key node of the brain reward circuitry [3]. Microglia regulate many aspects of central nervous system function, and may disrupt dopaminergic function in response to peripheral nerve injury [4]. The aim of this study was to investigate whether microglia in the NAcc contribute to decreased motivation and dopamine hypofunction after peripheral nerve injury.

Methods

Male and female C57BL/6 mice (n=9 per group) underwent spared nerve injury (SNI) or sham surgery. Using the Feeding Experimentation Device (FED3.1) [2] that allows 24 h recording, mice were submitted to an operant task between 3 and 4 weeks after surgery in which they nose poke for sucrose pellets on a progressive ratio. To define the causal role of microglia, Cx3cr1-CreERT mice were crossed with floxed R26-LSL-hm4Di-DREADD mice. During the whole period of the progressive ratio task, the DREADD agonist compound 21 was microinjected once a day (5mM/uL) in the NAcc through an implanted guide cannula. Control animals were SNI Cre-negative mice. CD11b immunoreactivity was quantified in NAcc from male and female Sprague Dawley rats at days 0,7 and 28 days after chronic constriction injury (N=4 per group). To correlate dopaminergic transport and receptor expression, we quantified levels of dopamine receptors D1/D2 and transporters DAT/VMAT via Western blot and compared SNI to sham animals.

Results

In mice spared nerve injury reduced the ratio of pokes/pellets [Two-Way ANOVA: F (1, 24)=10.59 P=0.003] and breakpoint mean [Two-Way ANOVA: F (1, 25)=14.95 P<0.001] in the sucrose self-administration task. The total amount of sucrose pellets consumed remained unchanged [P=0.06]. Densitometry analysis indicated a sustained upregulation of CD11b in the NAcc of CCI rats when comparing 7 and 28 days to naïve (day 0) [One Way ANOVA: F (2, 8)=60.32 P<0.0001]. Results of the DREADD-inhibition of microglia will be presented. Western blot analysis revealed a decrease in dopamine receptor D2 in mice with SNI, compared to sham controls [T-test P=0.022] with a non-statistically significant reduction in dopamine receptor D1 [T-test P=0.05]. No statistical differences in the dopamine transporters VMAT2 and DAT were detected [T-Test P=0.07 and P=0.08 respectively].

Conclusions

Spared nerve injury decreased motivation in a progressive ratio task using a feeding experimentation device in both male and female mice. The total amount of pellets consumed remained the same, indicating that the nerve injury increased efficiency to earn sucrose pellets. Microglia turned reactive in the NAcc of rats with peripheral nerve injury in both male and female rats, suggesting that reactive microglia may exert effects on motivated behavior. D2 receptor expression was downregulated in the NAcc, suggesting that peripheral nerve injury reduces dopamine signaling. Future works will focus on detecting microglia reactivity in the NAcc and manipulating microglia using DREADDs.

References

1.Tang, B.W., et al., Reciprocal interaction between depression and pain: results from a comprehensive bidirectional Mendelian randomization study and functional annotation analysis. Pain, 2022. 163(1): p. E40-E48.

2.Norris, M.R., et al., Spared nerve injury decreases motivation in long-access homecage-based operant tasks in mice. Pain, 2023.

3. Schwartz, N., et al., Chronic pain. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens. Science, 2014. 345(6196): p. 535-42.

4.Felger, J.C. and M.T. Treadway, Inflammation Effects on Motivation and Motor Activity: Role of Dopamine. Neuropsychopharmacology, 2017. 42(1): p. 216-241.

5.Kroenke, K., et al., Reciprocal Relationship Between Pain and Depression: A 12-Month Longitudinal Analysis in Primary Care. Journal of Pain, 2011. 12(9): p. 964-973.

Presenting Author

Rafael Cazuza

Poster Authors

Rafael Cazuza

PhD

UT-MD Anderson Cancer Center

Lead Author

E-mail

Sever Zagrai

UT - MD Anderson Cancer Center

Lead Author

E-mail

Anamaria Grieco

UT - MD Anderson Cancer Center

Lead Author

E-mail

Jane Morphett

University of Adelaide

Lead Author

E-mail

Michail Laoumtzis

University of Adelaide

Lead Author

E-mail

Michael Lacagnina

Cincinnati Children's Hospital Medical Center

Lead Author

E-mail

Rajasekaran Mahalingam

UT-MD Anderson Cancer Center

Lead Author

E-mail

Mark Hutchinson

University of Adelaide

Lead Author

E-mail

Topics

  • Models: Chronic Pain - Neuropathic