Chronic neuropathic pain is a refractory symptom in clinical practice due to nervous injury or inflammation

and affects millions of people all over the world. Although the neuronal functioning of pain pathways has been studied for many years

the induction and maintenance of this non-adaptive

pathological pain is still poorly understood. Recent evidence indicates that protease-activated receptors （PARs） participate in the initiation and maintenance of neuropathic pain and play a key role in mediating the interactions of nerve cells. Firstly

following nerve injury

alterations in neuron and neuron function induce an abnormal increase of some neurotransmitters and neuromodulators

such as substance P （SP）

calcitonin gene-related peptide （CGRP）

prostaglandins

kinins

and so on. Such abnormal factors can act on neuron reversely and then induce pain sensation directly

or activate glial cells （astrocytes and microglia） mediated by PARs

which trigger and accelerate the progress of neuropathic pain. Secondly

when the noxious factors invade

glial cells are activated as the first barrier of nervous system and secret many neuroinflammatory factors. These inflammatory factors have effects on PARs （especially PAR1 and PAR2） in the neurons around

and then aggravate the status of pain. Thirdly

in the progress of neuroinflammatory pain

microglia is activated first and initiates the status of pain

and then inflammatory factors and complements from microglia activate astrocytes and maintain or make the pain worse. All of these actions is protective to neurons first

but then turns to a kind of nociception and forms the feeling of pain under the continuous noxious stimuli. Conclusively

PARs may play an important role in the formation and maintenance of chronic pain through mediating the interactions among nerve cells

which may be a novel target in the study and control of neuropathic pain. This article focuses on recent developments of PARs in the progress of neuropathic pain

and provides a framework for addressing the major questions for the future.