Abstract
Neurotensin (NT) is an endogenous tridecapeptide in the central nervous system. NT-containing neurons and NT receptors are widely distributed in the spinal dorsal horn (SDH), indicating their possible modulatory roles in nociception processing. However, the exact distribution and function of NT, as well as NT receptors (NTRs) expression in the SDH, have not been well documented. Among the four NTR subtypes, NTR2 is predominantly involved in central analgesia according to previous reports. However, the expression and function of NTR2 in the SDH has not yet been directly elucidated. Specifically, it remains unclear how NT-NTR2 interactions contribute to NT-mediated analgesia. In the present study, by using immunofluorescent histochemical staining and immunohistochemical staining with in situ hybridization histochemical staining, we found that dense NT- immunoreactivity (NT-ir) and moderate NTR2-ir neuronal cell bodies and fibers were localized throughout the superficial laminae (laminae I-II) of the SDH at the light microscopic level. In addition, γ-aminobutyric acid (GABA) and NTR2 mRNA were colocalized in some neuronal cell bodies, predominantly in lamina II. Using confocal and electron microscopy, we also observed that NT-ir terminals made both close contacts and asymmetrical synapses with the local GABA-ir neurons. Second, electrophysiological recordings showed that NT facilitated inhibitory synaptic transmission but not glutamatergic excitatory synaptic transmission. Inactivation of NTR2 abolished the NT actions on both GABAergic and glycinergic synaptic release. Moreover, a behavioral study revealed that intrathecal injection of NT attenuated thermal pain, mechanical pain, and formalin induced acute inflammatory pain primarily by activating NTR2. Taken together, the present results provide direct evidence that NT-containing terminals and fibers, as well as NTR2-expressing neurons are widely distributed in the spinal dorsal horn, GABA-containing neurons express NTR2 mainly in lamina II, GABA coexists with NTR2 mainly in lamina II, and NT may directly increase the activity of local inhibitory neurons through NTR2 and induce analgesic effects.
Highlights
Nociceptive information is transferred from the periphery to the spinal dorsal horn (SDH) or trigeminal nucleus caudalis dorsal horn neurons via primary afferent termination
Our previous study showed that NTR2immunoreactive rostral ventromedial medulla (RVM) neurons that project to SDH receive NTergic descending projecting fibers and terminals originating from the periaqueductal gray (PAG) (Wang et al, 2014)
The results suggest that intrathecal application of NT could alleviate the thermal pain threshold in intact mice
Summary
Nociceptive information is transferred from the periphery to the spinal dorsal horn (SDH) or trigeminal nucleus caudalis dorsal horn neurons via primary afferent termination. Several classical amino acid neurotransmitters, such as glutamate, γ-aminobutyric acid (GABA) and glycine, as well as some neuropeptides, such as substance P (SP), calcitonin gene-related peptide (CGRP), and neurotensin (NT), are localized in the dorsal horn, indicating their possible roles in the transmission and modulation of nociception (Todd, 2010). Four neurotensin receptor subtypes (NTR1-4) have been confirmed in the central nervous system (CNS). Among these subtypes, NTR1 and NTR2 are cloned and clarified as G-protein coupled 7-transmembrane receptors, while NTR3 and NTR4 are elusive and may exert functions unrelated to NT signaling (Vincent et al, 1999; Fassio et al, 2000; Sarret et al, 2003a,b). The morphological and functional analysis of NTR2 in the dorsal horn remains largely unknown
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