Molecular and electrophysiological changes in the prefrontal cortex–amygdala–dorsal periaqueductal grey pathway during persistent pain state and fear-conditioned analgesia

Butler, Ryan K.; Nilsson-Todd, Linda; Cléren, Carine; Léna, Isabelle; García, René; Finn, David P.

doi:10.1016/j.physbeh.2011.05.028

Cited by 24 publications

(18 citation statements)

References 41 publications

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“…Given the exploratory nature of the investigation, this small number of target regions was used to minimise the problem of multiple comparisons. The target regions chosen were selected, firstly, as anatomical connections between each of them and the mPFC have been shown across a range of species [28]–[32], and secondly due to these connections being known, through work in both humans and non-human animals, to involve glutamate to some degree [22]–[26], [33]. In addition, the regions were selected as they have been implicated in disorders such as schizophrenia and depression [6], [34]–[36] and as they are of interest as components of what has been termed the core and para-core limbic systems that underlie fundamental stimulus processing [14], [37], [38].…”

Section: Introductionmentioning

confidence: 99%

“…This was based upon the prior knowledge that glutamate-related connections between the mPFC and the subcortical regions of interest exist [22]–[26], [33] and that glutamate has been implicated in inter-regional communication in vivo in humans [10]. As the relationship between functional and structural connectivity is complex [8], [39], no hypotheses were proposed in this regard.…”

Section: Introductionmentioning

confidence: 99%

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Glutamate Concentration in the Medial Prefrontal Cortex Predicts Resting-State Cortical-Subcortical Functional Connectivity in Humans

et al. 2013

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Communication between cortical and subcortical regions is integral to a wide range of psychological processes and has been implicated in a number of psychiatric conditions. Studies in animals have provided insight into the biochemical and connectivity processes underlying such communication. However, to date no experiments that link these factors in humans in vivo have been carried out. To investigate the role of glutamate in individual differences in communication between the cortex – specifically the medial prefrontal cortex (mPFC) – and subcortical regions in humans, a combination of resting-state fMRI, DTI and MRS was performed. The subcortical target regions were the nucleus accumbens (NAc), dorsomedial thalamus (DMT), and periaqueductal grey (PAG). It was found that functional connectivity between the mPFC and each of the NAc and DMT was positively correlated with mPFC glutamate concentrations, whilst functional connectivity between the mPFC and PAG was negatively correlated with glutamate concentration. The correlations involving mPFC glutamate and FC between the mPFC and each of the DMT and PAG were mirrored by correlations with structural connectivity, providing evidence that the glutamatergic relationship may, in part, be due to direct connectivity. These results are in agreement with existing results from animal studies and may have relevance for MDD and schizophrenia.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Glutamate Concentration in the Medial Prefrontal Cortex Predicts Resting-State Cortical-Subcortical Functional Connectivity in Humans

et al. 2013

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“…However, In addition to the PAG-RVM system, the dorsal reticular nucleus (DRt) and caudal lateral ventrolateral medulla (VLM) have also been reported to be involved in modulation of descending pain[65]. Neurons that project along the prefrontal cortex (PFC)–amygdala–PAG pathway have been implicated in mediating descending pain[46] and the PAG also receives inputs from the hypothalamus, PFC, and anterior cingulate cortex (ACC), which plays a major role in mediating pain[60]. Thus, we cannot deny the role of hypothalamus, PFC, ACC, DRt and VLM on this descending pathway.…”

Section: Discussionmentioning

confidence: 99%

“…and mounted in a stereotaxic frame (Zenda, Austin, Texas, USA. As reported, the guide cannula (RWD Life Science, Shenzhen, China) was implanted into the right CeLC—2.0 mm rostrally, 4.2 mm laterally, and 7 mm ventrally[11, 24, 40, 41] or the right ventrolateral periaqueductal grey(vlPAG) -7.6 mm rostrally, -0.5 mm laterally, and 5 mm ventrally [42–45] toward the bregma[46] and fixed to the skull with dental acrylic. A dummy cannula (RWD Life Science, Shenzhen, China) that inserts into the guide cannula, served to reduce the incidence of occlusion.…”

Section: Methodsmentioning

confidence: 99%

CaMKIIα may modulate fentanyl-induced hyperalgesia via a CeLC-PAG-RVM-spinal cord descending facilitative pain pathway in rats

Yin

Chen

et al. 2017

PLoS ONE

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Each of the lateral capsular division of central nucleus of amygdala(CeLC), periaqueductal gray (PAG), rostral ventromedial medulla(RVM) and spinal cord has been proved to contribute to the development of opioid-induced hyperalgesia(OIH). Especially, Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) in CeLC and spinal cord seems to play a key role in OIH modulation. However, the pain pathway through which CaMKIIα modulates OIH is not clear. The pathway from CeLC to spinal cord for this modulation was explored in the present study. Mechanical and thermal hyperalgesia were tested by von Frey test or Hargreaves test, respectively. CaMKIIα activity (phospho-CaMKIIα, p-CaMKIIα) was evaluated by western blot analysis. CaMKIIα antagonist (KN93) was micro-infused into CeLC, spinal cord or PAG, respectively, to evaluate its effect on behavioral hyperalgesia and p-CaMKIIα expression in CeLC, PAG, RVM and spinal cord. Then the underlying synaptic mechanism was explored by recording miniature excitatory postsynaptic currents (mEPSCs) on PAG slices using whole-cell voltage-clamp methods. Results showed that inhibition of CeLC, PAG or spinal CaMKIIα activity respectively by KN93, reversed both mechanical and thermal hyperalgesia. Microinjection of KN93 into CeLC decreased p-CaMKIIα expression in CeLC, PAG, RVM and spinal cord; while intrathecal KN93 can only block spinal but not CeLC CaMKIIα activity. KN93 injected into PAG just decreased p-CaMKIIα expression in PAG, RVM and spinal cord, but not in the CeLC. Similarly, whole-cell voltage-clamp recording found the frequency and amplitude of mEPSCs in PAG cells were decreased by KN93 added in PAG slice or micro-infused into CeLC in vivo. These results together with previous findings suggest that CaMKIIα may modulate OIH via a CeLC-PAG-RVM-spinal cord descending facilitative pain pathway.

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“…and held in a stereotaxic frame (Zenda, Austin, TX), as previously reported (Han et al, 2010;Sarhan et al, 2013;Zhang et al, 2013), A guide cannula (RWD Life Science, Shenzhen, China) was implanted toward the CeLC in the right hemisphere, using the following coordinates (in mm): 2.2 caudal to bregma, 4.2 lateral to midline, and depth 7.5 according to the Paxinos and Watson flat skull coordinate system (Butler et al, 2011). A 33-gauge dummy cannula was inserted in each guide cannula to avoid clogging.…”

Section: Intra-celc Cannulation and Microinjectionmentioning

confidence: 99%

Inhibition of CaMKII in the Central Nucleus of Amygdala Attenuates Fentanyl-Induced Hyperalgesia in Rats

Yin

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Opioid-induced hyperalgesia (OIH) is a less-studied phenomenon that has been reported in both preclinical and clinical studies. Although the underlying cause is not entirely understood, OIH is a real-life problem that affects millions of patients on a daily basis. Research has implicated the important contribution of Ca 21 / calmodulin-dependent protein kinase IIa (CaMKIIa) to OIH at the level of spinal nociceptors. To expand our understanding of the entire brain circuitry driving OIH, in this study we investigated the role of CaMKIIa in the laterocapcular division of the central amygdala (CeLC), the conjunctive point between the spinal cord and rostro-ventral medulla. OIH was produced by repeated fentanyl administration in the rat. Correlating with the development of mechanical allodynia and thermal hyperalgesia, CaMKIIa activity was significantly elevated in the CeLC in OIH. In addition, the frequency and amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs) in CeLC neurons were significantly increased in OIH. 2-[N-(2-hidroxyethyl)-N-(4-methoxybenzenesulfonyl)]-amino-N-(4-chlorocinnamyl)-N-methylbenzylamine, a CaMKIIa inhibitor, dose dependently reversed sensory hypersensitivity, activation of CeLC CaMKIIa, and mEPSCs in OIH. Taken together, our data for the first time implicate a critical role of CeLC CaMKIIa in OIH.

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Molecular and electrophysiological changes in the prefrontal cortex–amygdala–dorsal periaqueductal grey pathway during persistent pain state and fear-conditioned analgesia

Cited by 24 publications

References 41 publications

Glutamate Concentration in the Medial Prefrontal Cortex Predicts Resting-State Cortical-Subcortical Functional Connectivity in Humans

Glutamate Concentration in the Medial Prefrontal Cortex Predicts Resting-State Cortical-Subcortical Functional Connectivity in Humans

CaMKIIα may modulate fentanyl-induced hyperalgesia via a CeLC-PAG-RVM-spinal cord descending facilitative pain pathway in rats

Inhibition of CaMKII in the Central Nucleus of Amygdala Attenuates Fentanyl-Induced Hyperalgesia in Rats

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