Abstract
Endomorphin-2 (EM2) demonstrates a potent antinociceptive effect via the μ-opioid receptor (MOR). To provide morphological evidence for the pain control effect of EM2, the synaptic connections between EM2-immunoreactive (IR) axonal terminals and γ-amino butyric acid (GABA)/MOR co-expressing neurons in lamina II of the spinal trigeminal caudal nucleus (Vc) were investigated in the rat. Dense EM2-, MOR- and GABA-IR fibers and terminals were mainly observed in lamina II of the Vc. Within lamina II, GABA- and MOR-neuronal cell bodies were also encountered. The results of immunofluorescent histochemical triple-staining showed that approximately 14.2 or 18.9% of GABA-IR or MOR-IR neurons also showed MOR- or GABA-immunopositive staining in lamina II; approximately 45.2 and 36.1% of the GABA-IR and MOR-IR neurons, respectively, expressed FOS protein in their nuclei induced by injecting formalin into the left lower lip of the mouth. Most of the GABA/MOR, GABA/FOS, and MOR/FOS double-labeled neurons made close contacts with EM2-IR fibers and terminals. Immuno-electron microscopy confirmed that the EM2-IR terminals formed synapses with GABA-IR or MOR-IR dendritic processes and neuronal cell bodies in lamina II of the Vc. These results suggest that EM2 might participate in pain transmission and modulation by binding to MOR-IR and GABAergic inhibitory interneuron in lamina II of the Vc to exert inhibitory effect on the excitatory interneuron in lamina II and projection neurons in laminae I and III.
Highlights
The superficial laminae of the spinal trigeminal caudal nucleus (Vc), which is morphologically and functionally identical to the superficial laminae of the spinal dorsal horn and named medullary dorsal horn, play a critical role in the transmission and modulation of oro-facial nociceptive information conveyed via primary afferents in the trigeminal nerve (Dubner and Bennett, 1983; Todd, 2010; Wu et al, 2010)
A few MOR- and GABA-IR neuronal cell bodies were located in laminae I- III, especially in lamina II (Figures 1B,C ), but none of EM2-IR neuronal cell bodies were seen in the Vc (Figure 1A )
There are many inhibitory interneurons located in lamina II of the Vc and they are fundamental for nociceptive modulation (Dubner and Bennett, 1983; Todd et al, 1994; Wang et al, 2000, 2001; Todd, 2010; Wu et al, 2010; Yasaka et al, 2010)
Summary
The superficial laminae (lamina I and lamina II) of the spinal trigeminal caudal nucleus (Vc), which is morphologically and functionally identical to the superficial laminae of the spinal dorsal horn and named medullary dorsal horn, play a critical role in the transmission and modulation of oro-facial nociceptive information conveyed via primary afferents in the trigeminal nerve (Dubner and Bennett, 1983; Todd, 2010; Wu et al, 2010). Substance P (SP)-containing primary afferent terminals make asymmetric synapses with GABAergic interneurons in lamina II of the Vc (Wang et al, 2000) and GABAergic terminals originating from lamina II interneurons form symmetric synapses with projection neurons in lamina I and lamina III (Wang et al, 2001) These results suggest that inhibitory interneuronsplay an important role in regulating the excitatory neuronal activities in the Vc or spinal dorsal horn by releasing GABA (Dubner and Bennett, 1983; Todd et al, 1994; Wang et al, 2000, 2001; Todd, 2010; Wu et al, 2010; Yasaka et al, 2010)
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