Neuropathic pain is maladaptive pain condition and the maintaining mechanism is largely unclear. Pancreatitis-associated proteins (PAPs), the secretory proteins, belong to the calcium-dependent lectin gene superfamily. PAPs have been shown to play roles in the digestive system, as well as in neural regeneration after nerve injury. However, whether PAPs participate in pain development was still unclear.

In a study published in Journal of Neuroscience on Jan. 8, the researchers from Dr. ZHANG Xu’s Lab at CAS Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Institute of Neuroscience of the Chinese Academy of Sciences (CAS) and from Dr. BAO Lan’s Lab at Institute of Biochemistry and Cell Biology of CAS revealed a new pro- inflammatory factor pancreatitis-associated protein-I (PAP-I) in maintaining neuropathic pain. 

Using the rat spared nerve injure (SNI) model, the researchers found that peripheral nerve injury triggers the de novo expression of PAP-I only in dorsal root ganglia (DRG) neurons, the sizes of which shift from small to large and back to small ones, indicating the potential role of PAP-I in neuropathic pain. The increased PAP-I could be transported bi-directionally toward peripheral and central terminals.

To distinguish the function of PAP-I in two terminals, the researchers performed intrathecal injection and intraplantar injection of PAP-I respectively to rats and determined the behavioral effect.

The results showed that intrathecal but not intraplantar application of PAP-I induced thermal and mechanical hyperalgesia, indicating that PAP-I is pro-nociceptive in the spinal cord. In contrast, behavioral test in PAP-I knockout rats with SNI surgery developed tactile allodynia within the first week, but tactile allodynia was alleviated significantly at Day 43, which means PAP-I is not necessary in the initiation but play a major role in long-term maintenance of tactile allodynia.

Furthermore, the researchers found the activation of microglia in spinal dorsal horn after PAP-I injection. Additional experiments confirmed PAP-I-CCR2-p38 MAPK pathway in microglia activation. Finally, an inhibition of microglia activation or CCR2 reversed PAP-I-induced thermal and mechanical hyperalgesia.

Taken together, the study showed that PAP-I mediates the neuron-microglial crosstalk after peripheral nerve injury and contributes to the maintenance of neuropathic pain.

Figure: PAP-I is induced in DRG neurons after peripheral nerve injury and transported to spinal dorsal horn, and then activates microglia via CCR2-p38 MAPK pathway, involving in the maintenance of neuropathic pain. (Image by CEBSIT)