Research from the University of Toronto suggests that a peptide inhibitor called ZIP could be crucial in zipping away some kinds of chronic pain.
The new research, led by Professor Min Zhuo of the University of Toronto’s Department of Physiology and published in the current edition of the journal Science, explores the role that the protein kinase M zeta (PKMζ) plays in storing “memories” of pain and therefore enhancing the sensation of pain. Blocking the effect of PKMζ through the use of a selective inhibitor called ζ-pseudosubstrate inhibitory peptide – or ZIP — blocked behavioral sensitization and nerve injury related to chronic pain.
Normal pain or physiological pain is an important warning signal to avoid potentially dangerous situations or environments. It is brief, and short-lasting. Chronic pain is different, as it persists for weeks, month or years due to spontaneous firing or overexcited pain-related neurons.
“What makes chronic pain difficult to treat is that these painful signals trigger long-term plastic changes in different cortical areas and form permanent bad ‘memory’. It explains why the treatment of chronic pain in areas like the spinal cord is often insufficient or ineffective,” said Zhuo, the Canada Research Chair in Pain and Cognition.
Most previous studies have focused on signalling proteins that trigger these plastic changes, while few have addressed the maintenance of plastic changes related to chronic pain. Zhuo and his colleagues, Professors Bong-Kiun Kaang at the Seoul National University and Graham Collingridge in Bristol University, turned to PKMζ because of its well-established role as a memory storage molecule in two areas of the brain crucial for sensory and taste memory – the hippocampus and the neocortex.
The forebrain region known as the anterior cingulate cortex (ACC) is a centre of a different form of pain – chronic pain or psychogenic (social) pain. Zhuo calls ACC the area where we experience “the unpleasantness of pain.”
“Injury caused by peripheral inflammation, nerve ligation or amputation causes long-term enhancement of neuronal activity in the ACC. However, the question of what molecule maintains these painful changes has been unclear,” he said.
Zhuo and his collaborators found that PKMζ was indeed activated in the ACC when subjects were experiencing peripheral nerve injury. That suggests that PKMζ can be a therapeutic target for the treatment of pain, and the use of ZIP successfully muted chronic pain.
“This finding opens up a new area for pain researchers, and our hope is it will yield new strategies to assist people who struggle daily with the challenges of chronic pain,” Zhuo said.