Autism Gene Improves Understanding of Reduced Pain Sensitivity

Individuals with autism spectrum disorders (ASDs) are known to suffer from reduced pain sensitivity. New research suggests this phenomenon can be linked to a specific gene that may represent a critical avenue for future medications designed to treat chronic pain.

By Thomas G. Ciccone

 

Patients with autism spectrum disorders (ASDs) are known to suffer from sensory abnormalities, including reduced pain perception.

Researchers now believe the phenomena may be explained by the detection of a certain protein found in the body’s primary sensory neurons, and the manner in which this protein interacts with a specific pain receptor. These findings could be the key to understanding pain dysfunction in ASD, and perhaps extend to improved treatments for chronic pain.

In a study published in Neuron,¹ researchers from Duke University conducted a series of tests on genetically-modified mice to see how the absence of a particular gene, SHANK3, caused inflammatory and neuropathic pain to be impaired.

The Role of SHANK3 in Pain Regulation

While many genes affect synaptic transmission in patients with ASDs,² the SHANK3 gene has been isolated as a driver for pain.³In a past studies, doctors found mice bred without the SHANK3 gene showed dysregulated glutamatergic synapses.^4,5 This dysregulation has been found in other conditions, such as fragile X syndrome, Rett syndrome, and Angelman syndrome.

The SHANK3 gene, which maps to a critical chromosome region called 22q13.3, has been identified as absent in humans, such as those with Phelan-McDermid syndrome, also referred to as 22q13.3 syndrome.⁶

“It is known that patients with deletion 22q13.3 syndrome have less pain. This chromosome deletion includes the entire gene of SHANK3,” Ru-Rong Ji, PhD, a professor at the department of anesthesiology and neurobiology at Duke University Medical Center in Durham, North Carolina, told Practical Pain Management.

“There was some indication, but pain has not been directly tested. It is also important to point out that all the previous studies focused on the central nervous system, whereas we focused on the peripheral nervous system in this study,” said Dr. Ji.

SHANK3 Absence Reduces Pain Sensitivity

In wild-type mice, SHANK3 isoforms appear in numerous places, including dorsal root ganglion (DRG), spinal cord, cerebellum, and cortex tissues. So Dr. Ji and his colleagues specially bred another group of mice with the entire SHANK3 protein coding sequence missing.⁷

While baseline pain levels in the mice appeared normal, SHANK3 mutant mice showed significantly impaired heat hyperalgesia that did not appear due to reduced inflammation. Another test using chronic constriction injury (CCI) found similar results, where SHANK3 mutant mice simply had less affinity for neuropathic pain compared to wild mice. But this couldn’t be explained by cell loss or deficient neuronal innervation.

Dr. Ji and his colleagues believe the explanation for the lower pain perception may have to do with the way SHANK3 interacts with a pain receptor called TRPV1. Pain researchers have been very interested in TRPVI for a while,^8,9 although up to this point, little insight has existed concerning the scaffold proteins by which TRPV1 processes pain information in the body.

SHANK3 Sets Up Path to Pain Center

“TRPV1 is key target for pain medicine,” said Dr. Ji. Indeed, the transduction molecule regulates the release of glutamate from presynaptic terminals in the spinal cord.¹⁰

But when SHANK3 was missing, Dr. Ji and his colleagues found compromised TRPV1-mediated synaptic plasticity; even when injected with a spinal intrathecal injection of capsaicin, mice that didn’t have the SHANK3 gene showed a marked reduction in spontaneous pain. This pathway also appeared to affect the extracellular signal-regulated kinase (pERK) located in the superficial dorsal horn neurons, a key role player in the development of central sensitization that characterizes persistent pain.¹¹

According to Dr. Ji, the research points to an important relationship between SHANK3 and TRPV1. Now, the prevailing theory is that certain gene mutations could cause a compromised relationship between these proteins, resulting in pain dysfunction.

The Potential for Breakthrough Therapies

Not only could this theory better help to explain why some patients with ASD’s suffer from reduced pain sensitivity, the relationship between SHANK3 and TRPV1 could be exploited for the development of highly specific pharmacological targets in the treatment of chronic pain conditions.

However, TRPV1 is a critical ion channel in the body, and directly targeting it can cause dangerous side effects, particularly hyperthermia, Dr. Ji told Practical Pain Management.

Instead, Dr. Ji believes that by targeting the interaction between SHANK3 and TRPV1, doctors may develop a novel technique for inhibiting nociceptive signaling. This would require doctors to understand far more about the specific sequences of proteins involved during the nociceptive processing that occurs between SHANK3 and TRPV1, which has become a primary objective for Dr. Ji, who is now is in the process of developing new reagents designed to block SHANK3/TRPV1 interaction.

In future research, Dr. Ji and his team aim to identify other autism-related genes and investigate how the genes may affect primary sensory neurons.

This research was supported in part by grants from the National Institutes of Health. The authors reported no relevant conflicts of interest.

EDITOR’S ADDENDUM: Autism Gene Clinial Trial

To date, some 50 genes have been identified that may play a role in autism, but 300 or more are believed involved. A landmark study–Simons Foundation Powering Autism Research for Knowledge (SPARK)—is being launched in 21 nationally recognized research institutions to identify biological mechanisms of autism and to identify genetic and environmental factors involved in the autism spectrum disorder.

To learn if there is a center in your area, or to pass along the opportunity to patients who may be interested in participating in the study, go to: www.sparkforautism.org