Pavlovian fear memory induced by activation in the anterior cingulate cortex

Identifying higher brain central region(s) that are responsible for the unpleasantness of pain is the focus of many recent studies. Here we show that direct stimulation of the anterior cingulate cortex (ACC) in mice produced fear-like freezing responses and induced long-term fear memory, including contextual and auditory fear memory. Auditory fear memory required the activation of N-methyl-D-aspartate (NMDA) receptors in the amygdala. To test the hypothesis that neuronal activity in the ACC contributes to unpleasantness, we injected a GABA(A )receptor agonist, muscimol bilaterally into the ACC. Both contextual and auditory memories induced by foot shock were blocked. Furthermore, activation of metabotropic glutamate receptors in the ACC enhanced behavioral escape responses in a noxious hot-plate as well as spinal nociceptive tail-flick reflex. Our results provide strong evidence that the excitatory activity in the ACC contribute to pain-related fear memory as well as descending facilitatory modulation of spinal nociception

A brain-based pain facilitation mechanism contributes to painful diabetic polyneuropathy.

The descending pain modulatory system represents one of the oldest and most fundamentally important neurophysiological mechanisms relevant to pain. Extensive work in animals and humans has shown how a functional imbalance between the facilitatory and inhibitory components is linked to exacerbation and maintenance of persistent pain states. Forward translation of these findings into clinical populations is needed to verify the relevance of this imbalance. Diabetic polyneuropathy is one of the most common causes of chronic neuropathic pain; however, the reason why ∼25–30% of patients with diabetes develop pain is not known. The current study used a multimodal clinical neuroimaging approach to interrogate whether the sensory phenotype of painful diabetic polyneuropathy involves altered function of the ventrolateral periaqueductal grey—a key node of the descending pain modulatory system. We found that ventrolateral periaqueductal grey functional connectivity is altered in patients suffering from painful diabetic polyneuropathy; the magnitude of which is correlated to their spontaneous and allodynic pain as well as the magnitude of the cortical response elicited by an experimental tonic heat paradigm. We posit that ventrolateral periaqueductal grey-mediated descending pain modulatory system dysfunction may reflect a brain-based pain facilitation mechanism contributing to painful diabetic polyneuropathy.Funding for this work was generously provided from the following sources: National Institute for Health Research Oxford Biomedical Research Centre, Medical Research Council of Great Britain and Northern Ireland, the Wellcome Trust (London, UK) and the Innovative Medicines Initiative Joint Undertaking (Brussels, Belgium), under grant agreement no 115007 resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution. D.L.B. and A.C.T. are members of the DOLORisk consortium funded by the European Commission Horizon 2020 (ID633491). D.L.B. and A.C.T. are members of the International Diabetic Neuropathy Consortium, the Novo Nordisk Foundation (Ref. NNF14SA0006). D.L.B. is a senior Wellcome clinical scientist (Ref. 202747/Z/16/Z). The project was supported by a strategic award from the Wellcome (Ref. 102645). A.R.S., D.L.B., and I.T. are members of the Wellcome Pain Consortium (Ref. 102645). A.C.T. is an Honorary Research Fellow of the Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa