Mechanical pain : discovered a protein in the membrane of sensory neurons involved in pain feeling

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Researchers at McGill University have discovered that a protein found in the membrane of our sensory neurons are involved in our capacity to feel mechanical pain, laying the foundation for the development of powerful new analgesic drugs.

The study, published in Cell, is the first to show that TACAN, a highly conserved protein among vertebrates whose function remained unclear, is in fact involved in detecting mechanical pain by converting mechanical pressures into electric signals.

Using molecular and cellular approaches with electrophysiology, Reza Sharif-Naeini, a professor in McGill’s Department of Physiology, and his team were able to establish that TACAN is found on the membrane of pain sensing cells where it forms tunnel like pores, a structure known as an ion channel.

The researchers also created a mouse model where TACAN could be “turned off,” making the animals significantly less sensitive to painful mechanical stimuli.

“This demonstrates that TACAN contributes to sensing mechanical pain,” says Sharif-Naeini, who is also the study’s senior author.

A decade-long search

About 70 years ago, scientists imagined that tiny sensors might be responsible for providing our brain with useful information about our environment, explaining our sense of touch or our capacity to feel pain when pinched.

These sensors have since been discovered to be ion channels – pore like structures capable of translating mechanical pressures exerted on a cell into electrical signals that travel to the brain to be processed – a phenomenon known as mechanotransduction.

This phenomenon has been shown to be central in several physiological processes such as hearing, touch and the sensation of thirst. But the identity of the sensor responsible for mechanical pain remained elusive.

About 70 years ago, scientists imagined that tiny sensors might be responsible for providing our brain with useful information about our environment, explaining our sense of touch or our capacity to feel pain when pinched.

Because “most of the pain we feel – a pinch or a stubbed toe – is mechanical in nature,” Sharif-Naeini said that competition to find the newly discovered sensor was fierce.

With the rampant problem of opioid overuse, the finding has practical implications for people who suffer from chronic pain.

Patients with conditions such as osteoarthritis, rheumatoid arthritis or neuropathic pain often develop mechanical allodynia, a condition where mechanical pain receptors become overly sensitive.

Trivial things such as walking or a light touch thus become extremely painful, leading to a significant reduction in the quality of their lives.

“Now that we have identified the sensor associated with mechanical pain, we can start designing new powerful analgesic drugs that can block its action.

This discovery is really exciting and brings new hope for novel pain treatment,” adds Sharif-Naeini.

Funding: This work was supported by the Canadian Institutes of Health Research and the Groupe d’étude des protéines membranaires.


Neuropathic pain, a complex and chronic condition, is often associated with various pathologies including multiple sclerosis (MS) [1] and spinal cord injury (SCI) [2]. It remains the most challenging type of pain to treat, since conventional therapies are frequently ineffective.

Multiple sclerosis is an inflammatory, demyelinating disease of the central nervous system (CNS), whose precise etiology is still unknown [3]. Although the disease has been primarily characterized by motor deficits, chronic pain is a disabling symptom experienced by 60% of MS patients [45].

Chronic pain develops secondary to demyelination, neuroinflammation, and axonal damage in the CNS [6]. Similarly, chronic pain is common among individuals sustaining a SCI and affects quality of life [7].

The complex and vast cascade of events that follows spinal cord (SC) trauma causes pathological alterations at the lesion site but also in regions remote from the injury epicenter and rostral or caudal to the lesion site [8].

This can lead to neuropathic pain originating above, below, or at the level of the injury [9]. Evidence suggests that hyperactivation of second order sensory neurons in the dorsal horn (DH) of the SC is an important mechanism underlying neuropathic pain [10]. Effectors released by activated glia and/or infiltrating immune system cells, especially cytokines, including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor α (TNFα) have been implicated in the hyperactivation of DH neurons [1112].

Despite many advances, the mechanisms underlying neuropathic pain have not been fully characterized and the molecular events that result in the hyperactivation of neurons are inadequately defined.

Therefore, further investigations are needed to identify novel targets that contribute to pain mechanisms. The discovery of new targets could facilitate the design of therapeutic approaches that alleviate neuropathic pain more effectively.

Recent investigations in our laboratory indicated that plasma membrane calcium ATPase 2 (PMCA2) could play an important new role in mechanisms of pain processing in the DH of the SC [1314]. PMCA2 belongs to a family of calcium extrusion pumps present in a variety of cells [1517].

Various PMCA isoforms participate in the regulation of intracellular calcium levels during physiological and pathological conditions [1821]. Four PMCA isoforms have been described: PMCA1 and 4 are expressed ubiquitously, whereas the distributions of PMCA2 and PMCA3 are more restricted [2223].

In the CNS, PMCA2 and PMCA3 are primarily expressed in neurons [2425]. PMCA2 is also expressed in DH neurons, which receive pain messages from the dorsal root ganglia (DRG) and convey them to the brain [24].

Earlier reports from our laboratory demonstrated that adult, female PMCA2-heterozygous (PMCA2+/−) mice show increased mechanical pain sensitivity when compared to female, wild-type (PMCA2+/+) littermates [13]. Furthermore, lower PMCA2 expression in the DH of female PMCA2+/− mice was paralleled by specific changes in the expression of select glutamate receptors implicated in pain processing [13].

Since PMCA2 expression was not detected in the DRG, where primary sensory neurons reside, the findings led to the postulate that reduced PMCA2 expression in the DH corresponds with increased mechanical pain sensitivity. It is important to note that these previous studies assessed evoked pain responses in genetically modified mice that did not sustain injury or were not affected by disease.

As the involvement of PMCA2 in DH pain mechanisms during injury or disease has not been investigated, studies were undertaken to examine the role of PMCA2 in pathological pain using two distinct mouse models of injury or disease. One of these animal models is experimental autoimmune encephalomyelitis (EAE), a clinically relevant mouse model that mimics MS pathology [26].

Although EAE is primarily characterized by progressive motor deficits leading to paralysis, increased pain sensitivity has also been observed [2728]. The second is a murine SC contusion injury model, which causes paralysis and chronic pain [29]. We assessed whether the manifestation of pain in EAE and SCI is associated with a reduction in PMCA2 levels in the DH, and we identified the triggers that decrease PMCA2 expression in SC neurons, in vitro.

Conclusions

The present studies establish a link between PMCA2 expression in the DH and increased pain sensitivity in animal models of MS and SCI. It is proposed that PMCA2 plays a role in pain processing in the DH by inducing changes in intracellular Ca2+, which can affect the hyperexcitability of DH neurons and increase pro-nociceptive gene transcription.

Effectors released by inflammatory cells and activated glia and, in particular, IL-1β could trigger a reduction in PMCA2 levels in DH neurons. It is worth noting that we have previously reported that PMCA2 is also decreased in the ventral horn motor neurons during EAE [2471] and that the decrease in PMCA2 increases the vulnerability of motor neurons to injury and death [6172]. Thus, restoration of PMCA2 in the SC could alleviate not only pain but also motor deficits during EAE.


Source:
McGill University

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