Abstract
The central medial nucleus (CM), a prominent cell group of the intralaminar nuclei (ILN) of the thalamus, and the ventrolateral periaqueductal gray matter (vlPAG) are two major components of the medial pain system. Whether vlPAG and CM are input sources of nociceptive information to the basolateral amygdala (BLA) and whether they are involved in neuropathic pain regulation remain unclear. Clarifying the hierarchical organization of these subcortical nuclei (vlPAG, CM, and BLA) can enhance our understanding on the neural circuits for pain regulation. Behavioral test results showed that a CM lesion made by kainic acid (KA) injection could effectively alleviate mechanical hyperalgesia 4, 6, and 8 days after spared nerve injury (SNI) surgery, with the symptoms returning after 10 days. Morphological studies revealed that: (1) the CM received afferents from vlPAG and sent efferents to BLA, indicating that an indirect vlPAG–CM–BLA pathway exists; (2) such CM–BLA projections were primarily excitatory glutamatergic neurons as revealed by fluorescence in situ hybridization; (3) the fibers originated from the CM-formed close contacts with both excitatory and inhibitory neurons in the BLA; and (4) BLA-projecting CM neurons expressed Fos induced by SNI and formed close contacts with fibers from vlPAG, suggesting that the vlPAG–CM–BLA indirect pathway was activated in neuropathic pain conditions. Finally, the vlPAG–CM–BLA indirect pathway was further confirmed using anterograde and monosynaptic virus tracing investigation. In summary, our present results provide behavioral and morphological evidence that the indirect vlPAG–CM–BLA pathway might be a novel pain pathway involved in neuropathic pain regulation.
Highlights
Neuropathic pain is caused by disorders of, or damage to, the nervous system
Under spared nerve injury (SNI) conditions, the mechanical hyperalgesia was alleviated after the kainic acid (KA) lesion of central medial nucleus (CM), indicating that CM might play an important role on the formation of neuropathic pain
In order to prove that the ventrolateral periaqueductal gray matter (vlPAG)–CM–basolateral amygdala (BLA) pathway was involved in the modulation of neuropathic pain, we used anterograde and retrograde tract-tracing methods combined with Fos staining to find out whether the CM relaying neurons in the vlPAG-CM-BLA pathway were activated under SNI conditions
Summary
Neuropathic pain is caused by disorders of, or damage to, the nervous system. Its refractory nature and the lack of effective treatment strategies make it a major challenge (Ciaramella, 2019). Whether CM is another important source of pain information for the BLA remains unknown. Recent studies of the vlPAG have focused on its role in the descending pain pathway (Huang et al, 2019; Lau et al, 2020). To clarify the communications among vlPAG, CM, and BLA, we hypothesized that there was an indirect vlPAG–CM–BLA ascending pathway. This pathway might be involved in neuropathic pain modulation as an important source of nociceptive information for the BLA. To test this hypothesis, behavioral and morphological investigations were conducted in the present study
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