Studies Related to Neural Circuits in Neuropathic Pain

The brain nuclei and neural circuits behind neuropathic pain are both complex and large. Currently, nuclei involved in the modulation of injurious sensations in neuropathic pain have been found to be present in almost all brain regions, such as the PAG and RVM in the brainstem region, the LH and PVT in the midbrain, as well as the amygdala, the anterior cingulate gyrus, and the PFC in the cerebrum.

Some nuclear networks, when a linked feedback-regulated neural loop is abnormal, the overall pain regulatory balance is altered, leading to the onset of pain. In addition, due to the heterogeneity of neuron types distributed between different brain nuclei, different or even opposite behavioral outcomes often occur in the same nucleus or circuit. Therefore, studying nerve conduction and analyzing changes in neural activity associated with neuropathic pain can help to further our understanding of the pathophysiological mechanisms of pain.

Creative Biolabs discusses research related to neural circuits in neuropathic pain as well as provides assays or research tools related to neural circuit research.

Mechanisms of Neural Circuits in Neuropathic Pain

The perception of neuropathic pain can be traced to the complex network of neural circuits that are intricately involved in the development and maintenance of this condition. These circuits include peripheral sensory neurons, spinal cord neurons, and higher central nervous system neurons.

Research over the past decade has significantly deepened the comprehension of neuropathic pain's complex etiology. A significant revelation is the crucial transmission of neural signals between the peripheral, spinal, and central levels.

Fig. 1 Overview of peripheral and central changes contributing to neuropathic pain.¹

• Peripheral Mechanisms and Sensory Neurons
  Peripheral mechanisms in neuropathic pain primarily revolve around the damaged sensory neurons. Studies reveal that following nerve injury, an array of changes from novel ion channel expressions, structural variations to expanded receptive fields in sensory neurons, unfold in these peripheral nerve endings, directly contributing to pain hypersensitivity.
• Spinal Cord Neurons
  Spinal cord dorsal horn neurons have come into the limelight for their versatile role in mediating pain. Post nerve injury, these neurons exhibit physiological changes, including enhanced excitability and alterations in synaptic connections. Peripheral pain signals are thus amplified as they traverse along this neural pathway.
• Central Nervous System and Glial Cells
  Ascending the neural ladder, the central nervous system serves as the pinnacle of this signal transmission. Accumulating evidence highlights the role of brain-derived neurotrophic factors and central sensitization in modulating chronic pain. Additionally, glial cells, especially astrocytes and microglia, have advanced from passive players to active contributors engaging in bi-directional communication with neurons and shaping the neuropathic pain landscape.

Common Neuropathic Circuits in Neuropathic Pain

• PAG-RVM: PAG initiates endogenous pain modulatory systems and projects to the RVM. vlPAG sends glutamatergic projections to the RVM, and sustained activation of metabotropic glutamate receptors in PAG can increase pain thresholds and inhibit chronic neuropathic pain by regulating RVM cell activity. Elimination of projections from vlPAG to the RVM can lead to the generation of neuropathic pain.
  PAG-RVM neural circuits can exert downward inhibitory and facilitatory pathways, respectively, to bi-directionally regulate the development of neuropathic pain.
  • PAG neurons anatomically and functionally project to the RVM and exert a descending facilitatory effect on neuropathic pain mice.
  • In a chemotherapy-induced neuropathic pain model, growth inhibitory neurons from the PAG to the RVM promoted neuropathic pain.
• VTA-NAc: DA neuronal projections from the VTA to the NAc are a central part of the midbrain reward circuitry and have been the focus of scientists studying pain neural circuits. In recent years, however, the understanding of the involvement of the VTA-NAc DA circuit in the modulation of pain sensation has varied considerably between studies. There is heterogeneity in the involvement of VTA neurons or VTA-NAc circuits in the modulation of pain sensation.
  • In neuropathic pain model mice, the excitability of VTA-DA neurons projecting to the NAc was significantly reduced, and optogenetic stimulation of VTA-DA neurons significantly relieved pain.
  • In contrast, optogenetic inhibition of dopamine release from the VTA to the NAc in VTA-NAc DA neurons in CCI mice reversed CCI-induced nociceptive hypersensitivity to thermal injury.
• LPB-CeA: Most GABAergic inputs to the LPB are derived from and innervated by the CeA. In a neuropathic pain model, increased LPB neuronal activity is associated with a decrease in inhibitory GABAergic inputs, and activation of this pathway inhibits pain behavior. In addition, LPB neurons can transmit hurtful sensory information and negative emotions to the CeA. LPB and CeA are bi-directionally modulated at the level of brain circuits that together mediate either upstream injury signaling or downstream pain modulation information.
• PVT-vmPFC: The vmPFC is a key node in cortical and subcortical networks that plays a critical role in altering the meaning of pain. It was found that the vmPFC receives glutamatergic projections from the PVT and converts pain signals into anxiety signals.
• mPFC-NAc: DA was imported from VTA to mPFC and modulated neuropathic pain-related behaviors in mice. In addition, a key output target of the PFC is NAc. in a rat model of persistent neuropathic pain, optogenetic activation of the PFC produced significant analgesia and attenuated affective symptoms of pain. Projections to NAc may mediate this analgesic function.

Emerging Therapeutic Strategies Targeting Neural Circuits

Our advancing understanding of the neural circuits involved in neuropathic pain has paved the way for the development of novel therapeutic strategies aimed at restoring physiologic pain processing and alleviating symptoms. Pharmacological interventions targeting specific ion channels, neurotransmitter receptors and signaling pathways have shown promise in preclinical models and clinical trials. Many current therapies aim at attenuating neuron excitability and modulating neurotransmitter release to restore neural homeostasis.

Neuropathic pain's intricate etiology has been a fascinating puzzle for researchers worldwide. As we continue to uncover the pivotal role of neural circuitry in neuropathic pain, Creative Biolabs is committed to further advancing our understanding of neural circuits in neuropathic pain and their therapeutic implications.

Reference

1. Meacham, Kathleen, et al. "Neuropathic pain: central vs. peripheral mechanisms." Current pain and headache reports 21 (2017): 1-11.

For Research Use Only. Not For Clinical Use.