Genetic evidence of the function of Phox2a-expressing anterolateral system neurons in the transmission of chronic pain

The development of the chronic neuropathic pain state often originates at the level of peripheral sensory neurons, whose abnormal function elicits central sensitization and maladaptive plasticity in the nociceptive circuits of the spinal dorsal horn. These changes eventually reach supraspinal areas bringing about cognitive and affective co-morbidities of chronic pain such as anxiety and depression. This transmission presumably relies on the function of spinal projection neurons at the origin of the anterolateral system (AS). However, the identity of these neurons and the extent of their functional contribution remain unknown. Here, we asked these questions in the context of the mouse AS neurons that require the transcription factor Phox2a for their normal target connectivity and function in transmitting acute nociceptive information to the brain. To this end, we examined the effects of a spinal cord-specific loss of Phox2a (Phox2a(cKO)) on the development of central sensitization evoked by the spared nerve injury (SNI) model of chronic pain. We found that SNI-treated Phox2a(cKO) mice developed normal reflexive spinal responses such as mechanical allodynia evidenced by a decreased withdrawal threshold to von Frey filament stimulation and dynamic brush. On the other hand, Phox2a(cKO) attenuated the development of cold but not mechanical hyperalgesia, in behavioral paradigms that require the relay of nociceptive information to the brain. Furthermore, Phox2a(cKO) attenuated anxio-depressive-like behaviors evoked by SNI, measured by performance in the open field test and tail suspension test. Thus, Phox2a AS neurons play a critical role in the generation and maintenance of chronic neuropathic pain.

Automated summary

The development of chronic neuropathic pain states is influenced by abnormal function of peripheral sensory neurons, leading to central sensitization and maladaptive plasticity in the spinal dorsal horn. This eventually affects supraspinal areas and causes cognitive and affective co-morbidities such as anxiety and depression. The study focuses on the role of spinal projection neurons, specifically the Phox2a AS neurons, in the generation and maintenance of chronic neuropathic pain. The loss of Phox2a attenuated the development of cold hyperalgesia and anxio-depressive-like behaviors in mice, highlighting the critical role of Phox2a AS neurons in chronic pain.