The Effects of Dopamine Receptor Activation on Pain Mediation

RESEARCH ANALYSIS

The Effects of Dopamine Receptor Activation on Pain Mediation

Byron Espinoza, BS

Drexel University College of Medicine

SUMMARY POINTS

-       Dopamine cells are activated by opiates in individuals who are in a state of opiate withdrawal, not opiate naïve.

-       D2 receptor activation increases the mechanical and thermal threshold for pain while decreasing hyperalgesia and cold allodynia in neuropathic pain.

-       The antinociceptive action of opioids is dependent on adjuvant dopamine action on neurons.

-       Dopamine may diminish emotional perception of pain through its effects on the prefrontal cortex.

ANALYSIS

Background

Opioids mediate pain through the activation of opioid receptors, which have downstream effects on sensory neurons of the brain and spinal cord (1,2). In the motivation pathway, opioid receptors are located on presynaptic GABA-releasing terminals of the ventral tegmental area, which decrease GABA release and postsynaptic receptor activation. This GABA inhibition has different effects on opiate-naïve subjects vs opiate-deprived subjects. In a non-deprived state, GABA cells are activated by the lack of inhibitory GABA and then act on the tegmental pedunculopontine nucleus to reinforce behaviors; this pathway is dopamine independent. In an opiate-deprived state, GABA has an excitatory function, and therefore, its absence keeps GABA cells inhibited. This then has no action on the tegmental pedunculopontine nucleus and disinhibits dopamine cells, releasing dopamine onto the nucleus accumbens. Several studies have suggested that dopamine receptor activation plays a role in the analgesic effects of opioids (3).

Findings

Modern research has sought to understand how D1 and D2 agonists/antagonists affect acute pain behaviors in test subjects. Using D2 agonists such as Quinpirole and LY171555, mice were found to be more tolerant of painful stimuli. Specifically, D2 activation by Quinpirole inhibited pain behaviors in mice stimulated by formalin and capsaicin and decreased C-fiber firing of trigeminal neurons, which are involved in the afferent transfer of pain, burning, and itching (4). In a different study, Quinpirole also exhibited analgesic effects in mice with neuropathic pain. Mice with chronic constriction injury of their sciatic nerve were given an intraperitoneal injection of Quinpirole, which resulted in inhibition of cold and tactile allodynic responses (touch with von Frey monofilaments) for 3 and 48 hours, respectively. Continued injections of Quinpirole over the course of a week even led to a gradual improvement of symptoms (5).

Further studies focusing on dopamine’s effects on the brain highlight how D1 antagonists, such as SCH23390, and D2 antagonists, such as sulpiride, decrease the body’s ability to modulate pain. Researchers have reported that high-frequency stimulation in the VTA of a rodent’s brain releases dopamine into the prefrontal cortex, which suppresses nociceptive responses. The PFC is thought to play a role in how we modulate pain by influencing the emotional perception of pain. This response was successfully blocked by local microinjection of the D2 antagonist sulpiride. As shown in Figures 1 and 2 below, sulpiride stops HFS of the VTA from decreasing the nociceptive response of mice after mechanical stimulation, further confirming a relationship between dopamine and antinociception (6).

Figure 1: HFS to VTA suppresses nociceptive responses in VTA

Figure 2: Sulpiride inhibits the antinociceptive effects of VTA HFS

It is also noteworthy how the body’s natural production of dopamine assists opiates in their antinociceptive function. In a study that treated mice with heroin alongside SCH23390 (D1 antagonist) and Eticlopride (D2 antagonist), it was observed that the D1 antagonist decreased the latency with which mice reacted to painful stimuli, such as the hot plate test and tail immersion test. The hot plate test involves a plate of increasing temperature that causes a painful response from the mouse, such as hind paw-licking or jumping. The tail immersion test is similar in that a mouse’s tail is immersed in increasingly hot water until a reaction is recorded. As shown by the data in Figure 3 below, SCH23390 decreased painful reaction time after heroin treatment in a dose-dependent manner (4).

Discussion

Opioids are widely prescribed to treat acute and chronic pain, and they have proven to be an effective treatment option for many individuals. Unfortunately, the continued use and abuse of these drugs has brought on an epidemic that has taken countless lives and continues to do so. For this reason, there is an ever-growing dedication in research to implement social programs to combat opioid addiction or develop pharmacologic solutions to decrease dependence on opioids. The discovery of the antinociceptive effects of dopamine on pain, along with its synergistic effects with opioids, has led researchers to consider local DA agonists as potential adjuvants that could potentiate the effects of opioids and, ideally, allow physicians to prescribe lower doses. These studies have also helped researchers better understand the mechanisms of action of opioids, enabling more accurate scrutiny of their medicinal functionality. Long-term studies are needed to gain a deeper understanding of the effects of coadministration of DA agonists and opioids before they can be considered effective treatment options, but the growing dedication to this field shows promise.

REFERENCES

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2. Corder G, Castro DC, Bruchas MR, Scherrer G. Endogenous and Exogenous Opioids in Pain. Annu Rev Neurosci. 2018 Jul 8;41:453-473. doi: 10.1146/annurev-neuro-080317-061522. Epub 2018 May 31.

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7. Flores J. A., el Banoua F., Galán-Rodríguez B., Fernandez-Espejo E. Opiate anti-nociception is attenuated following lesion of large dopamine neurons of the periaqueductal grey: critical role for D1 (not D2) dopamine receptors. Pain. 2004;110(1):205–214. doi: 10.1016/j.pain.2004.03.036.