“Backache, leg pain, neck pain...” Researchers in biomedicine who often work long hours at their desks should know that pain is actually an unpleasant response of the body to injured tissues or potential injuries, which is a complex physiological and psychological activity and one of the most common symptoms in clinical practice. So, what new research ideas can there be about “pain”?!

Today, we will share an article with high IF of 21.2 published in the journal Nature Neuroscience, entitled “An ACC-VTA-ACC positive-feedback loop mediates the persistence of neuropathic pain and emotional consequences”. We can explore the research design ideas on the topic of “pain” through this case.

1. Research background

1.1 Maladaptive changes in the plasticity of peripheral nervous system (such as sensitization of peripheral nociceptors) and central nervous system (including central sensitization) may lead to chronic pain.

1.2 Tricyclic antidepressants can alleviate the sensory and emotional symptoms of neuropathic pain through unknown mechanisms.

1.3 The mesolimbic dopamine (DA) pathway mediates brain regions involved in emotional and motivational functions.

1.4 Pharmacological targeting of the DA pathway influences the responsiveness to opioid and non-opioid analgesics in the treatment of chronic pain.

2. Technical routes

3. Research results

3.1 Reduced activity of VTA^DA neurons mediates anxiety-depression-like behaviors and abnormal pain in neuropathic pain

3.2 Increased ACC^Glu-VTA transmission in neuropathic pain

3.3 ACC^Glu neurons dominate VTA^DA neurons through local GABAergic transmission

3.4 Feedback modulation via VTA^DA-ACC projections

3.5 ACC^Glu-VTA^GABA-VTA^DA-ACC^Glu forms a positive-feedback loop

3.6 The ACC-VTA-ACC feedback loop mediates the persistence of neuropathic pain

3.7 Targeting the intersection points within the ACC-VTA-ACC circuit can alleviate persistent pain

3.8 D2Rs as a dual therapeutic target for neuropathic pain

4. Research conclusion

This research confirmed the mutual neuronal circuits between ACC and VTA that mediates the mutual exacerbation of hyperalgesia and dyskinesia and their emotional consequences, thereby regulating the chronic neuropathic pain. ACC^Glu projected on VTA indirectly suppresses VTA^DA via local VTA^GABA, which is enhanced following nerve injury. VTADA neuron in turn projects on ACC, and transmits feedback information on emotional changes through synapses with the initial ACC^Glu neurons. Hence, ACC^Glu-VTA^GABA-VTA^DA-ACC^Glu positive-feedback loop modulates the development and maintenance of persistent pain and comorbid anxiety-depression-like behaviors. The ultimate findings reveal that in a mouse model of neuropathic pain, interrupting this feedback loop can alleviate acute and long-term hyperalgesia and anxiety-depression-like behavior.