Neuroscience. 2019 May 15;406:376-388. doi: 10.1016/j.neuroscience.2019.03.034.

Dopamine D1 and D3 receptor modulators restore morphine analgesia and prevent opioid preference in a model of neuropathic pain.

Rodgers HM1, Yow J1, Evans E1, Clemens S2, Brewer KL3.

1 Department of Emergency Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, United States of America.
2 Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, United States of America.
3 Department of Emergency Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, United States of America; Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, United States of America. Electronic address: brewerk@ecu.edu.

 

Abstract

A secondary consequence of spinal cord injury (SCI) is debilitating chronic neuropathic pain, which is commonly morphine resistant and inadequately managed by current treatment options. Consequently, new pain management therapies are desperately needed. We previously reported that dopamine D3 receptor (D3R) dysfunction was associated with opioid resistance and increases in D1 receptor (D1R) protein expression in the spinal cord. Here, we demonstrate that in a model of SCI neuropathic pain, adjuvant therapy with a D3R agonist (pramipexole) or D1R antagonist (SCH 39166) can restore the analgesic effects of morphine and reduce reward potential. Prior to surgery thermal and mechanical thresholds were tested in three groups of female rats (naïve, sham, SCI). After surgery, testing was repeated under the following drug conditions: 1) saline, 2) morphine, 3) pramipexole, 4) SCH 39166, 5) morphine + pramipexole, and 6) morphine + SCH 39166. Reward potential of morphine and both combinations was assessed using conditioned place preference. Following SCI, morphine + pramipexole and morphine + SCH 39166 significantly increased both thermal and mechanical thresholds. Morphine alone induced conditioned place preference, but when combined with either the D3R agonist or D1R antagonist preference was not induced. The data suggest that adjunct therapy with receptor-specific dopamine modulators can restore morphine analgesia and decrease reward potential and thus, represents a new target for pain management therapy after SCI.

Supplement: 

In the U.S. alone, an estimated 100 million people suffer from chronic pain (Nahin 2015), which has an annual economic impact of > $600 billion and affects “more Americans that diabetes, heart disease and cancer combined” (NIH 2018). Narcotic analgesics such as opioids are the among the most commonly prescribed class of medications in the United States with close to 11.5 million patients on a long-term opioid therapy (Daubresse, Chang et al. 2013). Although opioids are very effective in controlling pain and other sensory disorders under acute conditions, complications of chronic use include the development of tolerance, risk of addiction or dependence, misuse/abuse and accidental overdose (Rudd, Seth et al. 2016, Seth, Rudd et al. 2018).

 

According to the US Center for Disease Control and Prevention, nearly 400,000 deaths between 1999 and 2017 were linked to opioids and of these, 218,000 were linked to prescription opioids. In 2017 alone, some 47,600 people died of an opioid overdose, and nearly 200 people die every day from opioid overdoses.

 

Opioid tolerance is suspected to develop due to a dysfunction of μ-opioid receptor (MOR)- and dopamine (DA)-receptor mediated pathways in the brain. Data from our lab suggest that a dysfunction of the dopamine D3 receptor (D3R) system is associated with a morphine-resistant state and that use of a dopamine D3R agonist used in combination with the opioid agonist morphine can preserve or restore analgesia in an animal model. Both D3Rs and MORs are G-protein-coupled receptors (GPCRs), and many GPCRs, including opioid, cannabinoid, and dopamine receptors, can form associations between different receptor subtypes or with other GPCRs to form heteromeric complexes. The formation of these complexes, in turn, leads to the modulation of the properties of individual underlying subunits (protomers) (Gomes, Fujita et al. 2013).

 

Based on our preclinical data and the present study (Rodgers, Yow et al. 2019), we have developed a mechanistic model of presumed D3R and MOR interactions at the cell membrane that may play a role in the development of opioid tolerance, and its modulation of the D3R-MOR complex by adding D3R agonists. Both D3Rs and MORs have overlapping intracellular signaling pathways that each can contribute to pain relief. In a D3R-MOR heteromer configuration, morphine acts initially through the MOR pathway and exerts its beneficial and pain-relieving effect (Panel A). Over time, however, the MOR desensitizes and morphine doses have to be increased or are no longer effective (Panel B). Our data suggest that adding a D3R agonist to the morphine treatment is able to restore analgesic efficacy in an otherwise morphine-tolerant condition (Panel C).

 

Our data and model suggest that a combination of an opioid with a D3R agonist offers an additional tool that may be used in patients to preserve analgesia, prevent the development of tolerance and ultimately reduce the number of complications associated with continued opioid use in chronic pain conditions.

 

 

 

 

References:

Daubresse, M., H. Y. Chang, Y. Yu, S. Viswanathan, N. D. Shah, R. S. Stafford, S. P. Kruszewski and G. C. Alexander (2013). “Ambulatory diagnosis and treatment of nonmalignant pain in the United States, 2000-2010.” Med Care 51(10): 870-878.

Gomes, I., W. Fujita, M. V. Chandrakala and L. A. Devi (2013). “Disease-specific heteromerization of G-protein-coupled receptors that target drugs of abuse.” Prog Mol Biol Transl Sci 117: 207-265.

Nahin, R. L. (2015). “Estimates of pain prevalence and severity in adults: United States, 2012.” J Pain 16(8): 769-780.

NIH (2018). “NIH Research Portfolio Online Reporting Tools (RePORT).”

Rodgers, H. M., J. Yow, E. Evans, S. Clemens and K. L. Brewer (2019). “Dopamine D1 and D3 receptor modulators restore morphine analgesia and prevent opioid preference in a model of neuropathic pain.” Neuroscience 406: 376-388.

Rudd, R. A., P. Seth, F. David and L. Scholl (2016). “Increases in Drug and Opioid-Involved Overdose Deaths – United States, 2010-2015.” MMWR Morb Mortal Wkly Rep 65(50-51): 1445-1452.

Seth, P., R. A. Rudd, R. K. Noonan and T. M. Haegerich (2018). “Quantifying the Epidemic of Prescription Opioid Overdose Deaths.” Am J Public Health 108(4): 500-502.