Molecular mechanisms of pain in the anterior cingulate cortex

Department of Physiology, Faculty of Medicine, University of Toronto, University of Toronto Centre for the Study of Pain, Toronto, Ontario, Canada.
Journal of Neuroscience Research (Impact Factor: 2.59). 10/2006; 84(5):927-33. DOI: 10.1002/jnr.21003
Source: PubMed


It is well known that peripheral sensory stimuli, including pain, trigger a series of neuronal activities along the somatosensory pathways as well as the neuronal network in the high brain structures. These neuronal activities not only produce appropriate physiological responses but also induce long-term plastic changes in some of the central synapses. It is believed that long-term synaptic changes help the brain to process and store new information. Such learning is critical for animals and humans to gain new knowledge of changing environment, generate appropriate emotional responses, and avoid dangerous stimuli in the future. In the case of permanent injury, however, the brain fails to distinguish the difference between "useful" and painful stimuli. Long-term synaptic changes work against the system and at least in part contribute to chronic pain. In this short article, the possible molecular mechanisms for long-term plasticity within the anterior cingulate cortex (ACC) will be discussed and reviewed, and it is hypothesized that potentiation of excitatory responses within the ACC contributes to chronic pain and pain-related mental disorders.

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    • "In the ACC, it is revealed that activation of NMDA receptors and voltage-gated calcium channels may induce an increase in intracellular calcium level (Wei et al., 2006; Zhao et al., 2005). The rise in calcium leads to activation of various intracellular protein kinases and phosphatases (Wei et al., 2003), such as calcium-stimulated adenylyl cyclases (AC1 and 8) and calcium/calmodulin (CaM)-dependent protein kinases (PKC, CaMKII and CaMKIV) (Zhuo, 2006), which subsequently trigger MAPK/ERK-CREB signaling cascade and elicit cAMP response element-mediated gene expression including NMDA receptor subunit GluN2B (Rani et al., 2005; Zhuo, 2009), AMPAR GluA1 (Middei et al., 2013), BDNF (Ou and Gean, 2007; Tabuchi, 2008), etc., thereby resulting in the plastic up-regulation of them in protein synthesis (Kida, 2012; Kida and Serita, 2014). Such possible positive feedback is believed to play a crucial role in the formation of long-lasting plastic change in synaptic transmission within the ACC, and thus contribute to persistent pain (Descalzi et al., 2012a; Zhuo, 2007). "
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    ABSTRACT: The pathogenic mechanisms underlying neuropathic pain still remain largely unknown. In this study, we investigated whether spinal BDNF contributes to dorsal horn LTP induction and neuropathic pain development by activation of GluN2B-NMDA receptors via Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) phosphorylation in rats following spinal nerve ligation (SNL). We first demonstrated that spinal BDNF participates in the development of long-lasting hyperexcitability of dorsal horn WDR neurons (i.e. central sensitization) as well as pain allodynia in both intact and SNL rats. Second, we revealed that BDNF induces spinal LTP at C-fiber synapses via functional up-regulation of GluN2B-NMDA receptors in the spinal dorsal horn, and this BDNF-mediated LTP-like state is responsible for the occlusion of spinal LTP elicited by subsequent high-frequency electrical stimulation (HFS) of the sciatic nerve in SNL rats. Finally, we validated that BDNF-evoked SHP2 phosphorylation is required for subsequent GluN2B-NMDA receptors up-regulation and spinal LTP induction, and also for pain allodynia development. Blockade of SHP2 phosphorylation in the spinal dorsal horn using a potent SHP2 protein tyrosine phosphatase inhibitor NSC-87877, or knockdown of spinal SHP2 by intrathecal delivery of SHP2 siRNA, not only prevents BDNF-mediated GluN2B-NMDA receptors activation as well as spinal LTP induction and pain allodynia elicitation in intact rats, but also reduces the SNL-evoked GluN2B-NMDA receptors up-regulation and spinal LTP occlusion, and ultimately alleviates pain allodynia in neuropathic rats. Taken together, these results suggest that the BDNF/SHP2/GluN2B-NMDA signaling cascade plays a vital role in the development of central sensitization and neuropathic pain after peripheral nerve injury. Copyright © 2014 Elsevier Inc. All rights reserved.
    Neurobiology of Disease 11/2014; 73C:428-451. DOI:10.1016/j.nbd.2014.10.025 · 5.08 Impact Factor
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    • "Our previous studies show that neuropathic pain models induced long-term changes in excitatory synaptic transmission in the ACC neurons of adult mice [24,25]. Inactivation of the frontal cortex, including the ACC, by local lesions leads to the reduction of the nociceptive responses and aversive behaviors associated with chronic pain [26-29]. In situ hybridization brain atlas from the Allen Institute for Brain Science shows that N-, P/Q-, L-, T-, and R-type VGCCs are all expressed in the mouse ACC. "
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    ABSTRACT: Voltage gated calcium channels (VGCCs) are well known for its importance in synaptic transmission in the peripheral and central nervous system. However, the role of different VGCCs in the anterior cingulate cortex (ACC) has not been studied. Here, we use a multi-electrode array recording system (MED64) to study the contribution of different types of calcium channels in glutamatergic excitatory synaptic transmission in the ACC. We found that only the N-type calcium channel blocker omega-conotoxin-GVIA (omega-Ctx-GVIA) produced a great inhibition of basal synaptic transmission, especially in the superficial layer. Other calcium channel blockers that act on L-, P/Q-, R-, and T-type had no effect. We also tested the effects of several neuromodulators with or without omega-Ctx-GVIA. We found that N-type VGCC contributed partially to (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid- and (R)-Baclofen-induced synaptic inhibition. By contrast, the inhibitory effects of 2-Chloroadenosine and carbamoylcholine chloride did not differ with or without omega-Ctx-GVIA, indicating that they may act through other mechanisms. Our results provide strong evidence that N-type VGCCs mediate fast synaptic transmission in the ACC.
    Molecular Pain 11/2013; 9(1):58. DOI:10.1186/1744-8069-9-58 · 3.65 Impact Factor
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    • "The anterior cingulate cortex (ACC) is a heterogeneous brain area which is involved in sexual attraction [28], fear memory [29-35] and chronic pain [3-5,36-42]. The change of cingulate glutamatergic synaptic transmission in chronic pain conditions has been intensively studied [3-5,36-42], It has been demonstrated that strengthening of synaptic transmission in the ACC were mediated by both pre- and post synaptic mechanisms [4,41]. And also previous work showed that the intrinsic properties of pyramidal neurons in layers II/III of the ACC were affected by peripheral nerve injury [43]. "
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    ABSTRACT: The neurons in neocortex layer I (LI) provide inhibition to the cortical networks. Despite increasing use of mice for the study of brain functions, few studies are reported about mouse LI neurons. In the present study, we characterized intrinsic properties of LI neurons of the anterior cingulate cortex (ACC), a key cortical area for sensory and cognitive functions, by using whole-cell patch clamp recording approach. Seventy one neurons in LI and 12 pyramidal neurons in LII/III were recorded. Although all the LI neurons expressed continuous adapting firing characteristics, the unsupervised clustering results revealed five groups in the ACC, including: Spontaneous firing neurons; Delay-sAHP neurons, Delay-fAHP neurons, and two groups of neurons with ADP , ADP1 and ADP2. Using pharmacological approaches, we found that LI neurons receive both excitatory (mediated by AMPA, kainate and NMDA receptors), and inhibitory inputs (which were mediated by GABAA receptors). Our studies provide the first report characterizing the electrophysiological properties of neurons in LI of the ACC from adult mice.
    Molecular Pain 07/2012; 8(1):53. DOI:10.1186/1744-8069-8-53 · 3.65 Impact Factor
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