Forebrain medial septum sustains experimental neuropathic pain

Abstract

The present study explored the role of the medial septal region (MS) in experimental neuropathic pain. For the first time, we found that the MS sustains nociceptive behaviors in rodent models of neuropathic pain, especially in the chronic constriction injury (CCI) model and the paclitaxel model of chemotherapy-induced neuropathic pain. For example, inactivation of the MS with intraseptal muscimol (2 μg/μl, 0.5 μl), a GABA mimetic, reversed peripheral hypersensitivity (PH) in the CCI model and induced place preference in a conditioned place preference task, a surrogate measure of spontaneous nociception. The effect of intraseptal muscimol on PH was comparable to that seen with microinjection of the local anesthetic, lidocaine, into rostral ventromedial medulla which is implicated in facilitating experimental chronic nociception. Cellular analysis in the CCI model showed that the MS region sustains nociceptive gain with CCI by facilitating basal nociceptive processing and the amplification of stimulus-evoked neural processing. Indeed, consistent with the idea that excitatory transmission through MS facilitates chronic experimental pain, intraseptal microinjection of antagonists acting at AMPA and NMDA glutamate receptors attenuated CCI-induced PH. We propose that the MS is a central monitor of bodily nociception which sustains molecular plasticity triggered by persistent noxious insult.

Modulation of Septo-Hippocampal Neural Responses in Anesthetized and Behaving Rats by Septal AMPA Receptor Mechanisms

“…The procedure has been described previously (Lee et al, 2011 ; Ang et al, 2017 ; Ariffin et al, 2018 ). Briefly, rats were anesthetized with an isoflurane-oxygen mixture (5% for induction and 2% for maintenance) and mounted onto a stereotaxic frame with the surface of the skull in a horizontal plane.…”

“…The medial septal region (MS) is implicated in various aspects of behavior such as affect-motivation, cognition, behavioral arousal, and sensorimotor integration (Winson, 1978 ; Gray, 1982 ; Bland, 1986 , 2009 ; Givens and Olton, 1990 ; Nagahara and McGaugh, 1992 ; Gray and McNaughton, 2000 ; Bland and Oddie, 2001 ; Ma et al, 2002 ; McNaughton and Corr, 2004 ; McNaughton et al, 2006 ; Shin et al, 2009 ; Ang et al, 2015 , 2017 ; Wang et al, 2015 ). Additionally, our laboratory has also shown that MS is a nodal region in mediating persistent unprovoked nociception and peripheral hypersensitivity (PH) to external stimulus following peripheral injury in rodents (Khanna and Sinclair, 1992 ; Khanna, 1997 ; Zheng and Khanna, 2001 ; Tai et al, 2006 ; Lee et al, 2011 ; Ang et al, 2015 ; Ariffin et al, 2018 ). Functionally, the MS regulates hippocampal theta wave activity which is a 4–12 Hz extracellular sinusoidal waveform that provides the basis for temporal organization of information in the hippocampus (Leung, 1984 ; Bland, 1986 ; Buzsáki, 2002 ).…”

“…The septal glutamatergic neuropil and intraseptal glutamatergic transmission have been proposed to affect a wide range of septo-hippocampal functions, including theta activation, sensorimotor behaviors, PH, and cognition (Elvander-Tottie et al, 2006 ; Fuhrmann et al, 2015 ; Ariffin et al, 2018 ). Although stimulation of intraseptal afferent in theta range induced AMPA currents, the role of these receptors in theta mediation still remains unclear (Armstrong and MacVicar, 2001 ; Leung and Shen, 2004 ; Bland et al, 2007 ).…”

“…Although stimulation of intraseptal afferent in theta range induced AMPA currents, the role of these receptors in theta mediation still remains unclear (Armstrong and MacVicar, 2001 ; Leung and Shen, 2004 ; Bland et al, 2007 ). While there is evidence of AMPAR-mediated nociceptive process in experimental neuropathic pain (Ariffin et al, 2018 ), there is a lack of information on its role in acute nociception within the septo-hippocampal network.…”

Medial septum neurokinin- and somatostatin-sensitive mechanisms mediate sensorimotor and nociceptive behaviours

“…Cortical implantations: Survival surgery was performed under aseptic conditions using stereotaxic technique as previously described (Ang et al, 2015;Ariffin et al, 2018;Lee et al, 2011). Briefly, anesthesia was induced and maintained with 5% and 2% isoflurane, respectively.…”