Dopamine's Crucial Role in "Priming" Chronic Pain
Commentary by Theodore J. Price, PhD
Chronic pain is hard to treat and even harder to explain. In the brainstem, various pain modulators control how the body perceives pain. Researchers are beginning to map the mechanics of chronic pain, to explore how sensory neurons can become hypersensitive, sparking prolonged and exaggerated responses to stimuli, well after an injury has healed.
Findings from a new study found one of the body’s most important neurotransmitters was integral in the development of chronic pain—dopamine.1
Doctors have been aware of dopamine’s significance to the body’s nociceptive processes. Found in a specific area of the hypothalamus, dopaminergic (DA) neurons are known to affect nociceptive functioning in the spinal dorsal horn.2
While this research points to new avenues of inquiry, dopamine is already the focus of pharmaceutical agents in the setting of pain management. For over a century, astute practitioners have used dopaminergic drugs to treat chronic pain. Usually classified as ‘stimulants,’ they potentiate opioids and minimize their use.
The study reported here is basic scientific evidence that dopamine is critical to pain control, and it helps validate the use of dopaminergic agents in chronic pain treatment. I believe that dopaminergic agents are underutilized in pain management and Practical Pain Management will feature articles on their use.
This phenomenon of neuronal plasticity, also called hyperalgesic priming, was first observed in rats. It may be a key model to better understanding chronic pain, which could lead to improved treatments for generalized pain disorders like fibromyalgia, as well as other ailments, like occupational overuse syndrome and tension-type headaches.3
In the current study, researchers created a lesion to target dopamine neurons in rats and see how hyperalgesic priming’s effects changed.1 To induce priming, the investigators produced a temporary inflammation into a rat’s hind paw, letting it resolve after a few days. Weeks later, the researchers administer a low dose of prostaglandin E2 (PGE2), an inflammatory cytokine, which elicits far greater hyperalgesia than warranted, in both duration and intensity of pain.
"We found that when dorsal horn neurokinin 1 receptor-positive neurons or descending serotonergic neurons were ablated before hyperalgesic priming, interleukin (IL)-6- and carrageenan-induced mechanical hypersensitivity was impaired, and subsequent PGE2 response was blunted," wrote the authors.
However, when these neurons were lesioned after hyperalgesic priming, "they had no effect on the PGE2 response, reflecting differential mechanisms driving plasticity in a primed state." This suggests dopamine’s descending circuitry is essential to hyperalgesic priming’s “maintenance” phase, which takes place after an initial inflammation has been inflicted and nociceptors have been primed for an exaggerated response to a subsequent insult.
Lasting Effects of Hyperalgesic Priming
Previous investigations have shown hyperalgesic priming can last for 3 weeks, without any further stimuli to maintain the plasticity.3 In this new study, the researchers saw the effect last for as long as 5 weeks. In reality, hyperalgesic priming could last for a lot longer, possibly months, according to Theodore J. Price, PhD, co-author of the study and an associate professor at the University of Texas at Dallas.
“We have shown that this priming effect lasts longer than has been shown before, and we have evidence that with more severe initial injuries, such as surgical incision, the priming effect lasts for several months,” Dr. Price said in an email interview with Practical Pain Management.
“We have also noticed that the effect lasts longer in certain strains of mice but we have not published those results yet. I imagine that there are mouse strains that would be susceptible to very long periods of priming even to minor injuries.”
Dopamine’s role in hyperalgesic priming originates from the central nervous system, and spinal dopamine D1/D5 receptors are essential to this pathway, said Dr. Price. In fact, administering a D1/D5 agonist to mice already primed with an initial stimulus elicited a mechanical hypersensitivity akin to using PGE2.
Highly expressed in the spinal dorsal horn,4 D1/D5 receptors have a neuron-specific expression pattern, so finding the postsynaptic targets of dopamine projections is the next major step, as they could very well be the neuroplastic changes induced by hyperalgesic priming.
“We think that the major targets are deep dorsal horn neurons and a population of neurons in the very far lateral areas of substantia gelatinosa,” which is a mass of neuroglia that caps the apex of the posterior grey column, said Dr. Price.
“We think this because that is where DAT (Dopamine Reuptake Transporter) staining is most intense around neurons, presumably indicating synaptic connections. We are trying to develop methods to fish out these neurons but we are not quite there yet.
“We are using pharmacological methods combined with histochemistry to try to identify them now, but we ultimately would like to use genetic methods. Interestingly, we already have a good deal of evidence that those neurons are GABAergic.”
Other Neurotransmitters’ Role
The researchers didn’t just focus on dopamine, though. They tested other neurotransmitters, as well, namely the monoamines serotonin and norepinephrine, similarly using targeted lesions to examine how they influenced the hyperalgesic priming model.
Serotonergic (5-HT) projections do facilitate nociceptive processing,5,6 but while the 5-HT lesion blunted the acute response to initial inflammation, there didn’t seem to be any effect on the subsequent PGE2 injection.
Likewise, LNE descending neurons also play a role in nociceptive processing, by promoting hypersensitivity to neuropathic pain,7 but NE neurons didn’t seem to be necessary for the maintenance of hyperalgesic priming, either.
Using a dopaminergic lesion, on the other hand, not only reversed the effects of hyperalgesic priming, it reversed the bilateral effects of priming on the contralateral hind paw.
Previous research has shown dopamine receptors to be altered in fibromyalgia, burning mouth syndrome, and atypical facial pain.8-10 Finding which dopamine receptors are relevant is of significant interest to Dr. Price, something that he continues to research, today.