A pathway from midcingulate cortex to posterior insula gates nociceptive hypersensitivity

Abstract

The identity of cortical circuits mediating nociception and pain is largely unclear. The cingulate cortex is consistently activated during pain, but the functional specificity of cingulate divisions, the roles at distinct temporal phases of central plasticity and the underlying circuitry are unknown. Here we show in mice that the midcingulate division of the cingulate cortex (MCC) does not mediate acute pain sensation and pain affect, but gates sensory hypersensitivity by acting in a wide cortical and subcortical network. Within this complex network, we identified an afferent MCC-posterior insula pathway that can induce and maintain nociceptive hypersensitivity in the absence of conditioned peripheral noxious drive. This facilitation of nociception is brought about by recruitment of descending serotonergic facilitatory projections to the spinal cord. These results have implications for our understanding of neuronal mechanisms facilitating the transition from acute to long-lasting pain.

Protein Kinase C Lambda Mediates Acid-Sensing Ion Channel 1a-Dependent Cortical Synaptic Plasticity and Pain Hypersensitivity

“…Unless otherwise stated, pain-related behavioral tests were performed at day 1, 3, 5, and 7 after the CFA injection. For neuropathic pain, we adopted a well-established spared nerve injury (SNI) model as previously described (Bourquin et al, 2006;Chen et al, 2015;Tan et al, 2017). Briefly, the mice were anesthetized with isoflurane, and an incision was made to the lateral skin surface of the thigh to expose the sciatic nerve and its branches.…”

“…Next, we tested whether ASIC1a antagonism has similar antihyperalgesic effects in other animal models of chronic pain. We used the well-established SNI model of neuropathic pain in adult mice as previously described (Bourquin et al, 2006;Tan et al, 2017). Post-treatment with intra-ACC administration of PcTx1 at 7 d after SNI significantly reversed the mechanical allodynia, with the analgesic effect lasting for at least 90 min (F (1,9) ϭ 26.94, p ϭ 0.0006, two-way repeated-measures ANOVA; Tukey's multiple-comparison test: saline vs PcTx1, p ϭ 0.0004, p Ͻ 0.0001, and p ϭ 0.0074 for 10, 30, and 90 min, respectively; Fig.…”

Etiology and Pharmacology of Neuropathic Pain

“…Multiple changes are observed in the pain matrix that includes the medial prefrontal cortex, nucleus accumbens, anterior cingulate cortex, insula, amygdala, periaqueductal gray, locus coeruleus, and rostroventral medulla (Schweinhardt and Bushnell, 2010;von Hehn et al, 2012;Zhang et al, 2015c;Peirs and Seal, 2016;Tan et al, 2017;Taylor et al, 2017). For example, synapses in the anterior cingulate cortex are altered after peripheral nerve injury, and LTP of glutamatergic transmission appears in the insula (Zhuo, 2016a).…”

A whole-brain connectivity map of mouse insular cortex

“…Rodent studies further demonstrated roles for the IC in multisensory (Gogolla, Takesian, Feng, Fagiolini, & Hensch, 2014; Rodgers, Benison, Klein, & Barth, 2008) and pain processing (Tan et al, 2017), representation of valence (Wang et al, 2018), learning and memory (Bermúdez-Rattoni, Okuda, Roozendaal, & McGaugh, 2005; Lavi, Jacobson, Rosenblum, & Lüthi, 2018), social interactions (Rogers-Carter et al, 2018), gustation (Peng et al, 2015; Wang et al, 2018), drug cravings and malaise (Contreras, Ceric, & Torrealba, 2007), and aversive states such as hunger, thirst, and anxiety (Gehrlach et al, 2019; Livneh et al, 2017, 2020).…”