Chronic pain states are now recognized to evolve much like memories do, but the specific mechanisms that initiate and maintain pain hypersensitivity are still emerging. New research in mice shows that descending dopaminergic modulation at the spinal cord level is required to maintain a “primed” state following inflammatory injury, rendering the animals vulnerable to future pain hypersensitivity.
Priming has been well described in primary nociceptors (Reichling and Levine, 2009), but less is known about priming in the spinal cord. Yves De Koninck, Institut Universitaire en Santé Mentale de Québec, Canada, who was not involved in the current work, said, “The authors have made an important contribution to the very intriguing concept that there is also a central mechanism to priming.”
Another novel aspect of the research, led by Theodore Price, University of Texas at Dallas, US, was the influence of dopamine in the spinal cord. Although dopamine has been implicated in chronic pain states before in animals, said Price, “what we have found suggests a wider pathology of the dopaminergic system in chronic pain.”
In a comment submitted to PRF, Stephen Hunt, University College London, UK, who was not involved in the new research, wrote, “Ted Price and his collaborators have uncovered an important new role for dopamine in generating persistent pain states and therefore revealed a possible therapeutic route for the alleviation of chronic pain states in patients....” (see full comment below).
The study was published April 22 in The Journal of Neuroscience.
First author Ji-Young Kim, University of Arizona, Tucson, US, and colleagues used a hyperalgesic priming model of chronic pain in which the inflammatory molecules interleukin 6 (IL-6) or carrageenan are injected into the hindpaw of mice, which causes mechanical hyperalgesia that resolves after several days. Seven days later, injection of prostaglandin E2 (PGE2), another inflammatory molecule, produced mechanical hyperalgesia lasting at least three days, whereas PGE2 injection in unprimed mice produced pain lasting only about an hour.
The researchers wanted to determine which neurons were responsible for this pathological pain plasticity. Projection neurons in the spinal dorsal horn that contain receptors for neurokinin 1 (NK1) were a leading candidate, because previously they had been implicated in chronic pain hypersensitivity in rodents. When the researchers ablated NK1 receptor-positive neurons with a targeted toxin two weeks before injecting mice with IL-6, the animals did not develop hypersensitivity to either IL-6 or to subsequent injection of PGE2, indicating that the neurons were required for induction of the pain plasticity state. Killing the neurons a week after IL-6 injection, however, had no effect—the mice still developed hypersensitivity in response to PGE2 injection, suggesting that NK1-positive neurons are not required for maintenance of hyperalgesic priming. That finding could help explain the failure of NK1 inhibitors to reverse established chronic pain in clinical trials, Price said.
Because the NK1 neurons were required for initiation of hyperalgesic priming but expendable for maintenance of the primed state, the researchers reasoned that one of two scenarios must be at play: either dorsal horn circuitry rearranged around NK1 neurons following priming, or descending modulation by supraspinal neurons influenced spinal pain processing independent of NK1 neurons. To determine which was the case, the team tested whether the priming effects extended to the animals' contralateral side—which they did. “If you prime one side,” Price said, “you can precipitate chronic pain sensitization contralaterally.” The involvement of both sides of the spinal cord, rather than just the affected side, indicates that higher brain centers might be involved. In addition, a facial grimace test indicated that pain hypersensitivity extended to the animals’ affective state. “In our view, that had to mean there was a central mechanism, and likely that would involve descending modulation.”
The best-known descending modulatory inputs to the spinal cord come from neurons that release serotonin or norepinephrine (for review of descending modulation of pain, see Ossipov et al., 2014). The investigators first ablated serotonergic neurons from the brainstem, which are known to have a pro-nociceptive influence in the spinal cord. When the neurons were lost before priming with IL-6, mechanical hyperalgesia was reduced both acutely and in response to subsequent injection with PGE2. After priming with IL-6, though, loss of serotonergic neurons did not prevent PGE2 from inducing a heightened pain response, showing that the neurons were not responsible for maintaining the primed state. Similar experiments in which the researchers ablated norepinephrinergic neurons from the locus coeruleus demonstrated that these cells were not required for maintaining priming, either.
Although still poorly understood, dopaminergic neurons from the hypothalamic A11 nucleus have recently been recognized to influence pain in the spinal cord (Taniguchi et al., 2011). When Price’s team killed dopaminergic neurons using the selective catecholamine toxin 6-OHDA, mice still exhibited mechanical hyperalgesia following injection of IL-6, but not after injection of PGE2 seven days later. When they created the dopamine lesion after IL-6 injection, when priming had been established, PGE2 still failed to induce mechanical hyperalgesia, whether it was delivered ipsilaterally or contralaterally. “We found that dopaminergic inputs were absolutely required for maintenance but played no role whatsoever in initiation,” of the primed state, Price said. “That was exciting because little is known about dopaminergic spinal inputs at all, and even less is known about them in pain states.”
The team next wanted to determine which type of dopamine receptors were responsible for maintenance of pain plasticity. A D2 receptor antagonist injected into the spinal cord when the paw was injected with PGE2 had no effect—the animals still displayed mechanical hypersensitivity indicative of priming—but intrathecal injection of a D1/D5 antagonist in primed animals reduced PGE2-induced mechanical hypersensitivity. Conversely, injection of a D1/D5 agonist in primed, but not control, mice produced a daylong hyperalgesic state even without PGE2 treatment, cementing a role for the receptors in preserving spinal pain plasticity.
A labile pain state?
The field of memory research has provided clues to how pain states become—and stay—chronic. A case in point is the phenomenon of reconsolidation, which has recently been extended to pain (Bonin and De Koninck, 2014). “When an event recalls a memory, synapses enter a labile state,” De Koninck explained. Through protein degradation and translation, a reconsolidation process maintains the memory. But if protein translation is blocked while the recall occurs, the memory can be erased.
The new work found that the dopamine-mediated primed state was subject to reconsolidation as well. IL-6-primed mice injected with PGE2 displayed mechanical hypersensitivity, but if a protein translation inhibitor was injected intrathecally at the same time as PGE2, the primed state was reversed: subsequent PGE2 did not induce hypersensitivity.
“I think we are scratching the tip of the iceberg here,” said De Koninck. “These findings suggest we have potential tools to tap into the system and reset the mode from hypersensitive to normal.” The real question for future work to tap that potential for therapeutic purposes, he added, will be to address which molecules play specific roles in initiating and maintaining chronic pain states, and when and how to target them.
With this new report, said Price, “we have found another really big piece of the puzzle.”
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.
Image credit: Ji-Young Kim and processed for artistic effect by Julianne Fowler