New pain mechanisms revealed for neurotoxin in spinal cord injury

November 23, 2015  

Riyi Shi

Riyi Shi
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WEST LAFAYETTE, Ind. – A toxin released by the body in response to spinal cord injuries increases pain by causing a proliferation of channels containing pain sensors, new research shows, and this hypersensitivity also extends to peripheral nerves in the limbs far from the injury site.

Findings could point to a new route for treating pain in people with spinal cord injuries, said Riyi Shi (pronounced Ree Shee), a professor of neuroscience and biomedical engineering in Purdue University's Department of Basic Medical Sciences, College of Veterinary Medicine and Weldon School of Biomedical Engineering.

A neurotoxin called acrolein is produced within the body after nerve cells are damaged, triggering a cascade of biochemical events thought to worsen the injury's severity. The research showed acrolein activates and likely causes a proliferation of pain receptors called TRPA1, or transient receptor potential ankyrin, contained in central and peripheral nerves in the limbs of research animals.

The proliferation of channels increases the number of binding sites for the toxin, evidently worsening pain. It is thought to cause a cell's genetic material to signal for over-production of TRPA1, resulting in hypersensitivity to pain in both the spinal cord and the limbs, Shi said.

"Amplification of sensory stimuli also occurs in the periphery, not only at the injury site, and this was not known before," he said. "The data suggest that acrolein has the capability to cause widespread sensory hypersensitivity and likely plays an essential role in neuropathic pain extending beyond the location of the original injury."

Findings are detailed in a research paper recently published online in the Journal of Neurochemistry. The research also showed that artificially increasing acrolein causes pain and increased TRPA1 even when there is no spinal cord injury.

"The fact that acrolein alone could lead to sensory hypersensitivity in the absence of mechanical damage suggests that it plays a fundamental role in the production of neuropathic pain," he said.

Revelations that acrolein worsens pain in peripheral nerves points to a potential new treatment approach, perhaps by stimulating nerve endings in extremities, he said. Another potential treatment strategy is reducing the concentration of acrolein using the drug hydralazine, which has been approved by the U.S. Food and Drug Administration for hypertension. The drug has been shown to reduce acrolein, pain, and TRPA1 expression following spinal cord injury in research animals.

The paper was authored by graduate students Jonghyuck Park, Lingxing Zheng, Glen Acosta, Sasha Vega-Alvarez and Breanne Muratori; former postdoctoral researcher Zhe Chen who worked with surgeon Peng Cao at Shanghai Jiao-Tong University in China; and Shi. 

Writer: Emil Venere, 765-494-4709, 

Source: Riyi Shi, 765-496-3018,

Note to Journalists: A copy of the research paper is available from Emil Venere, Purdue News Service, at 765-494-4709,


Acrolein contributes to TRPA1 up-regulation in peripheral and central sensory hypersensitivity following spinal cord injury    

Jonghyuck Park,*,† Lingxing Zheng,*,† Glen Acosta,* Sasha Vega-Alvarez,* Zhe Chen,‡ Breanne Muratori,† Peng Cao‡ and Riyi Shi*,†1

*Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana  

†Weldon School of Biomedical Engineering, Purdue University

‡Department of Orthopedics, Rui-Jin Hospital, School of Medicine, Shanghai Jiao-tong University, Institute of Trauma and Orthopedics, Shanghai, China

Corresponding author: Riyi Shi. E-mail: 

Acrolein, an endogenous aldehyde, has been shown to be involved in sensory hypersensitivity after rat spinal cord injury (SCI), for which the pathogenesis is unclear. Acrolein can directly activate a pro-algesic transient receptor protein ankyrin 1 (TRPA1) channel that exists in sensory neurons. Both acrolein and TRPA1 mRNA are elevated post SCI, which contributes to the activation of TRPA1 by acrolein and consequently, neuropathic pain. In the current study, we further showed that, post-SCI elevation of TRPA1 mRNA exists not only in dorsal root ganglias but also in both peripheral (paw skin) and central endings of primary afferent nerves (dorsal horn of spinal cord). This is the first indication that pain signaling can be over-amplified in the peripheral skin by elevated expressions of TRPA1 following SCI, in addition over-amplification previously seen in the spinal cord and dorsal root ganglia. Furthermore, we show that acrolein alone, in the absence of physical trauma, could lead to the elevation of TRPA1 mRNA at various locations when injected to the spinal cord. In addition, post-SCI elevation of TRPA1 mRNA could be mitigated using acrolein scavengers. Both of these attributes support the critical role of acrolein in elevating TRPA1 expression through gene regulation. Taken together, these data indicate that acrolein is likely a critical causal factor in heightening pain sensation post-SCI, through both the direct binding of TRPA1 receptor, and also by boosting the expression of TRPA1. Finally, our data also further support the notion that acrolein scavenging may be an effective therapeutic approach to alleviate neuropathic pain after SCI. Keywords: aldehyde, hydralazine, hyperreflexia, lipid peroxidation, proalgesic. J. Neurochem. (2015) 10.1111/jnc.13352 

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