Spinal sensory transmission is under descending biphasic modulation, and descending facilitation is believed to contribute to chronic pain. Descending modulation from the brainstem rostral ventromedial medulla (RVM) has been the most studied, whereas little is known about direct corticospinal modulation. Here, we found that stimulation in the anterior cingulate cortex (ACC) potentiated spinal excitatory synaptic transmission and this modulation is independent of the RVM. Peripheral nerve injury enhanced the spinal synaptic transmission and occluded the ACC-spinal cord facilitation. Inhibition of ACC reduced the enhanced spinal synaptic transmission caused by nerve injury. Finally, using optogenetics, we showed that selective activation of ACC-spinal cord projecting neurons caused behavioral pain sensitization, while inhibiting the projection induced analgesic effects. Our results provide strong evidence that ACC stimulation facilitates spinal sensory excitatory transmission by a RVM-independent manner, and that such top-down facilitation may contribute to the process of chronic neuropathic pain.

The dorsal medial prefrontal cortex (dmPFC) has been recognized as a key cortical area for nociceptive modulation. However, the underlying neural pathway and the function of specific cell types remain largely unclear. Here, we show that lesions in the dmPFC induced an algesic and anxious state. Using multiple tracing methods including a rabies-based transsynaptic tracing method, we outlined an excitatory descending neural pathway from the dmPFC to the ventrolateral periaqueductal gray (vlPAG). Specific activation of the dmPFC/vlPAG neural pathway by optogenetic manipulation produced analgesic and antianxiety effects in a mouse model of chronic pain. Inhibitory neurons in the dmPFC were specifically activated using a chemogenetic approach, which logically produced an algesic and anxious state under both normal and chronic pain conditions. Antagonists of the GABA_A receptor (GABA_AR) or mGluR1 were applied to the dmPFC, which produced analgesic and antianxiety effects. In summary, the results of our study suggest that the dmPFC/vlPAG neural pathway might participate in the maintenance of pain thresholds and antianxiety behaviors under normal conditions, while silencing or suppressing the dmPFC/vlPAG pathway might be involved in the initial stages and maintenance of chronic pain and the emergence of anxiety-like behaviors.

Neuropathic pain is a common clinical condition. Current treatments are often inadequate, ineffective, or produce potentially severe adverse effects. Understanding the mechanisms that underlie the development and maintenance of neuropathic pain will be helpful in identifying new therapeutic targets and developing effective strategies for the prevention and/or treatment of this disorder. The genesis of neuropathic pain is reliant, at least in part, on abnormal spontaneous activity within sensory neurons. Therefore, voltage-gated sodium channels, which are essential for the generation and conduction of action potentials, are potential targets for treating neuropathic pain. However, preclinical studies have shown unexpected results because most pain-associated voltage-gated channels in the dorsal root ganglion are down-regulated after peripheral nerve injury. The role of dorsal root ganglion voltage-gated channels in neuropathic pain is still unclear. In this report, we describe the expression and distribution of voltage-gated sodium channels in the dorsal root ganglion. We also review evidence regarding changes in their expression under neuropathic pain conditions and their roles in behavioral responses in a variety of neuropathic pain models. We finally discuss their potential involvement in neuropathic pain.

Emerging research implicates the participation of spinal dorsal horn (SDH) neurons and astrocytes in nerve injury-induced neuropathic pain. However, the crosstalk between spinal astrocytes and neurons in neuropathic pain is not clear. Using a lumbar 5 (L5) spinal nerve ligation (SNL) pain model, we testified our hypothesis that SDH neurons and astrocytes reciprocally regulate each other to maintain the persistent neuropathic pain states. Glial fibrillary acidic protein (GFAP) was used as the astrocytic specific marker and Fos, protein of the protooncogene c-fos, was used as a marker for activated neurons. SNL induced a significant mechanical allodynia as well as activated SDH neurons indicated by the Fos expression at the early phase and activated astrocytes with the increased expression of GFAP during the late phase of pain, respectively. Intrathecal administration of c-fos antisense oligodeoxynucleotides (ASO) or astroglial toxin L-α-aminoadipate (L-AA) reversed the mechanical allodynia, respectively. Immunofluorescent histochemistry revealed that intrathecal administration of c-fos ASO significantly suppressed activation of not only neurons but also astrocytes induced by SNL. Meanwhile, L-AA shortened the duration of neuronal activation by SNL. Our data offers evidence that neuronal and astrocytic activations are closely related with the maintenance of neuropathic pain through a reciprocal “crosstalk”. The current study suggests that neuronal and non-neuronal elements should be taken integrally into consideration for nociceptive transmission, and that the intervention of such interaction may offer some novel pain therapeutic strategies.

Long-term potentiation (LTP) is the key cellular mechanism for physiological learning and pathological chronic pain. In the anterior cingulate cortex (ACC), postsynaptic recruitment or modification of AMPA receptor (AMPAR) GluA1 contribute to the expression of LTP. Here we report that pyramidal cells in the deep layers of the ACC send direct descending projecting terminals to the dorsal horn of the spinal cord (lamina I-III). After peripheral nerve injury, these projection cells are activated, and postsynaptic excitatory responses of these descending projecting neurons were significantly enhanced. Newly recruited AMPARs contribute to the potentiated synaptic transmission of cingulate neurons. PKA-dependent phosphorylation of GluA1 is important, since enhanced synaptic transmission was abolished in GluA1 phosphorylation site serine-845 mutant mice. Our findings provide strong evidence that peripheral nerve injury induce long-term enhancement of cortical-spinal projecting cells in the ACC. Direct top-down projection system provides rapid and profound modulation of spinal sensory transmission, including painful information. Inhibiting cortical top-down descending facilitation may serve as a novel target for treating neuropathic pain.