Huntington-associated protein 1 inhibition contributes to neuropathic pain by suppressing Cav1.2 activity and attenuating inflammation

• Published in: Pain (Amsterdam) Vol. 164; no. 6; pp. e286 - e302
• Main Authors: Pan, JingYing, Zhao, YaYu, Sang, Rui, Yang, RiYun, Bao, JingYin, Wu, YongJiang, Fei, Ying, Wu, Jian, Chen, Gang
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer 01.06.2023
• Subjects: Animals; Brain-Derived Neurotrophic Factor - metabolism; Ganglia, Spinal - metabolism; Hyperalgesia; Mice; Neuralgia - metabolism; Rats; Rats, Sprague-Dawley; Spinal Cord Dorsal Horn - metabolism
• ISSN: 0304-3959; 1872-6623
• DOI: 10.1097/j.pain.0000000000002837

Although pain dysfunction is increasingly observed in Huntington disease, the underlying mechanisms still unknown. As a crucial Huntington-associated protein, Huntington-associated protein 1 (HAP1) is enriched in normal spinal dorsal horn and dorsal root ganglia (DRG) which are regarded as "primary sensory center," indicating its potential functions in pain process. Here, we discovered that HAP1 level was greatly increased in the dorsal horn and DRG under acute and chronic pain conditions. Lack of HAP1 obviously suppressed mechanical allodynia and hyperalgesia in spared nerve injury (SNI)-induced and chronic constriction injury-induced pain. Its deficiency also greatly inhibited the excitability of nociceptive neurons. Interestingly, we found that suppressing HAP1 level diminished the membrane expression of the L-type calcium channel (Cav1.2), which can regulate Ca 2+ influx and then influence brain-derived neurotrophic factor (BDNF) synthesis and release. Furthermore, SNI-induced activation of astrocytes and microglia notably decreased in HAP1-deficient mice. These results indicate that HAP1 deficiency might attenuate pain responses. Collectively, our results suggest that HAP1 in dorsal horn and DRG neurons regulates Cav1.2 surface expression, which in turn reduces neuronal excitability, BDNF secretion, and inflammatory responses and ultimately influences neuropathic pain progression.