From the AGA Journals

P2X7 receptor implicated in visceral pain caused by chronic pancreatitis

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A ‘cautionary message’

The traditional approach to treating pain in chronic pancreatitis is as if it were a “plumbing” problem – problems with ductal drainage. More recently, the emphasis has been on sensitization of the sensorineural system (“wiring”), in which the pain responses are greatly exaggerated. An additional consideration is whether this sensitization occurs in peripheral nerves that directly innervate the pancreas, or in the central nervous system, or both. This is clinically important because treatments directed at the periphery, e.g., pancreatectomy, may not be effective in patients in whom central sensitization is dominant.

Dr. Pankaj Jay Pasricha

The findings of Dr. Lui and colleagues show that spinal (hence central) sensitization is important in chronic pancreatitis pain, and that this may be mediated by nonneuronal cells (microglia) in the spinal cord via P2X7R, a nucleotide receptor. This is not surprising, given that this signaling system has shown to be important in other forms of chronic pain. However, some questions remain – is peripheral sensitization driving these changes?

Clearly the “drug” they have used (BBG) is relatively harmless, but it is not practical because it may not be safe in humans (apart from coloring them blue). BBG also affects other channels, notably neuronal voltage-dependent sodium channels. Nevertheless, this study does offer new insight into the pathogenesis of pain in chronic pancreatitis and by itself is an important cautionary message for the growing enthusiasm for total pancreatectomy. It also identifies potential new therapeutic targets for treatment of pain and will, it is hoped, stimulate engagement from the pharmaceutical industry that is developing drugs directed toward glial activation and in particular the P2X7 receptor.

Dr. Pankaj Jay Pasricha, AGAF, is professor of medicine, Johns Hopkins University School of Medicine, director of Johns Hopkins Center for Motility Disorders and Digestive Diseases, and professor of innovation management, The Carey Business School, Johns Hopkins University, Baltimore. He has no conflicts of interest.



A subtype of purinergic receptor on spinal microglial cells mediated visceral pain hypersensitivity in rats with chronic pancreatitis, and pharmacologic or genetic inhibition of this receptor improved hyperalgesia, according to a report in the November issue of Cellular and Molecular Gastroenterology and Hepatology.

“Our study may be the first to identify that P2X7 receptors in spinal microglia are upregulated in chronic pancreatitis, and that this upregulation is associated with the development of visceral hyperalgesia,” said Dr. Pei-Yi Liu at National Yang-Ming University in Taipei, Taiwan, and her associates. A common laboratory dye known as brilliant blue G, which is an antagonist of P2X7R, “not only attenuated but also prevented CP-related chronic visceral hyperalgesia,” the researchers reported.

Chronic pancreatitis causes intense, recurrent epigastric pain that is “difficult and frustrating” to control and can lead to malnutrition, narcotic analgesic addiction, and social and financial problems, said the researchers. Previously, they had linked visceral pain in murine CP to activation of spinal microglia, the main effector immune cells in the central nervous system. The molecular pathways remained unclear, but some research had implicated extracellular adenosine triphosphate (ATP) as well as purinergic receptors in the CNS. Because a purine receptor subtype known as P2X7 had been linked to neuropathic and inflammatory pain, the researchers wondered if it also facilitated visceral pain (Cell Mol Gastroenterol Hepatol. 2015 Jul 22. doi: 10.1016/j.jcmgh.2015.07.008). To explore that question, they created a CP model by injecting 2% trinitrobenzene sulfonic acid into the pancreatic ducts of male rats. They measured behavioral responses to mechanical and electrical stimulation and quantified spinal cord P2X7R levels with the help of standard laboratory assays. They also watched for changes in pain-related behaviors after blocking spinal cord P2X7R with brilliant blue G or knocking it down with short interfering RNA (siRNA).

Spinal P2X7R expression rose significantly after CP induction, as did levels of the OX-42 microglial marker in the dorsal horn of the spinal cord, said the investigators. Brilliant blue G and genetic knock down suppressed P2X7R expression, inhibited activation of spinal microglia, and “significantly attenuated” nociceptive behaviors, they added.

The researchers also pretreated some rats with brilliant blue G before inducing CP and saw that these rats exhibited significantly lower pain responses to mechanical and electrical stimuli compared with other CP rats. In fact, the nociceptive responses of the pretreated CP rats resembled those of non-CP control rats, the investigators said. Spinal tissue from pretreated rats also lacked signs of P2X7R upregulation, they noted.

Taken together, the data “indicate a critical role of P2X7R expressed in the spinal cord in the development of chronic visceral pain in CP,” concluded the researchers. Brilliant blue G inhibits voltage-gated sodium channels, which are known to contribute to chronic visceral pain, and “may represent an effective drug for the treatment of chronic pain in chronic pancreatitis patients,” they added.

The study was funded by Taipei Veterans General Hospital, National Science Council of Taiwan, and the Taiwan Ministry of Education Aim for Top University Grant. The investigators declared no competing interests.

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