Chronic pain is frequently associated with anxiety, depression, and cognitive dysfunction. This review discusses recent work in rodents that contributes to the understanding of their neurobiological links. Brain regions that contain circuits that mediate persistent changes in behavior that are caused by nerve injury or joint inflammation include the rostral anterior cingulate and other parts of the medial prefrontal cortex, the basolateral and central nucleus of the amygdala, and the nucleus accumbens. Functional changes, including increases in the activity within specific neuronal pathways and in the levels of specific synaptic components, that are associated with the behavior changes, or are in some cases necessary for them, have recently been identified. Broadly projecting modulatory systems and widely expressed factors such as cytokines and growth factors also contribute to pain-associated behavior. Integrating these observations and determining their causal relationships is now critical for the identification of therapeutic targets and the design of appropriate interventions.
Alba-DelgadoCLlorca-TorralbaMHorrilloIOrtegaJEMicoJASánchez-BlázquezP, and others. 2013. Chronic pain leads to concomitant noradrenergic impairment and mood disorders. Biol Psychiatry73:54–62.
2.
AlvaradoSTajerianMMillecampsMSudermanMStoneLSSzyfM.2013. Peripheral nerve injury is accompanied by chronic transcriptome-wide changes in the mouse prefrontal cortex. Mol Pain9:21.
3.
AustinPJBeyerKBembrickALKeayKA. 2010. Peripheral nerve injury differentially regulates dopaminergic pathways in the nucleus accumbens of rats with either “pain alone” or “pain and disability.” Neuroscience171:329–43.
4.
BarthasFSellmeijerJHugelSWaltispergerEBarrotMYalcinI.2015. The anterior cingulate cortex is a critical hub for pain-induced depression. Biol Psychiatry77:236–45.
5.
Cardoso-CruzHDouradoMMonteiroCMatosMRGalhardoV.2014. Activation of dopaminergic D2/D3 receptors modulates dorsoventral connectivity in the hippocampus and reverses the impairment of working memory after nerve injury. J Neurosci34:5861–73.
6.
Cardoso-CruzHLimaDGalhardoV.2013a. Impaired spatial memory performance in a rat model of neuropathic pain is associated with reduced hippocampus-prefrontal cortex connectivity. J Neurosci33:2465–80.
7.
Cardoso-CruzHSousaMVieiraJBLimaDGalhardoV.2013b. Prefrontal cortex and mediodorsal thalamus reduced connectivity is associated with spatial working memory impairment in rats with inflammatory pain. Pain154:2397–406.
8.
ChangPCPollema-MaysSLCentenoMVProcissiDContiniMBariaAT, and others. 2014. Role of nucleus accumbens in neuropathic pain: linked multi-scale evidence in the rat transitioning to neuropathic pain. Pain155:1128–39.
9.
ChenJSongYYangJZhangYZhaoPZhuXJ, and others. 2013. The contribution of TNF-α in the amygdala to anxiety in mice with persistent inflammatory pain. Neurosci Lett541:275–80.
10.
ChenTWangWDongYLZhangMMWangJKogaK, and others. 2014. Postsynaptic insertion of AMPA receptor onto cortical pyramidal neurons in the anterior cingulate cortex after peripheral nerve injury. Mol Brain7:76.
11.
CoveyWCIgnatowskiTAKnightPRSpenglerRN. 2000. Brain-derived TNFalpha: involvement in neuroplastic changes implicated in the conscious perception of persistent pain. Brain Res859:113–22.
12.
de FreitasRLSalgado-RohnerCJHallakJECde Souza CrippaJACoimbraNC. 2013. Involvement of prelimbic medial prefrontal cortex in panic-like elaborated defensive behaviour and innate fear-induced antinociception elicited by GABAA receptor blockade in the dorsomedial and ventromedial hypothalamic nuclei: role of the endocannabinoid CB1 receptor. Int J Neuropsychopharm16:1781–98.
13.
de NovellisVVitaDGattaLLuongoLBelliniGDe ChiaroM, others. 2011. The blockade of the transient receptor potential vanilloid type 1 and fatty acid amide hydrolase decreases symptoms and central sequelae in the medial prefrontal cortex of neuropathic rats. Mol Pain7:7.
14.
DelaneyAJCraneJWSahP.2007. Noradrenaline modulates transmission at a central synapse by a presynaptic mechanism. Neuron56:880–92.
15.
DellaroleAMortonPBrambillaRWaltersWSummersSBernardesD, and others. 2014. Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling. Brain Behav Immun41:65–81.
16.
DevoizelLAlvarezlPMonconduitlLDallellR.2012. Representation of dynamic mechanical allodynia in the ventral medial prefrontal cortex of trigeminal neuropathic rats. Eur J Pain15:676–82.
17.
DimitrovELTsudaMCCameronHAUsdinTB. 2014. Anxiety- and depression-like behavior and impaired neurogenesis evoked by peripheral neuropathy persist following resolution of prolonged tactile hypersensitivity. J Neurosci34:12304–12.
18.
DuricVMcCarsonKE. 2006. Persistent pain produces stress-like alterations in hippocampal neurogenesis and gene expression. J Pain7:544–55.
19.
FuYNeugebauerV.2008. Differential mechanisms of CRF1 and CRF2 receptor functions in the amygdala in pain-related synaptic facilitation and behavior. J Neurosci28:3861–76.
20.
GiordanoCCristinoLLuongoLSiniscalcoDPetrosinoSPiscitelliF, and others. 2012. TRPV1-dependent and -independent alterations in the limbic cortex of neuropathic mice: impact on glial caspases and pain perception. Cereb Cortex22:2495–518.
21.
GofferYXuDEberleSED’amourJLeeMTukeyD, and others. 2013. Calcium-permeable AMPA receptors in the nucleus accumbens regulate depression-like behaviors in the chronic neuropathic pain state. J Neurosci33:19034–44.
22.
GrégoireSWattiezASEtienneMMarchandFArdidD.2014. Monoarthritis-induced emotional and cognitive impairments in rats are sensitive to low systemic doses or intra-amygdala injections of morphine. Eur J Pharmacol735:1–9.
23.
HungKLWangSJWangYCChiangTRWangCC. 2014. Upregulation of presynaptic proteins and protein kinases associated with enhanced glutamate release from axonal terminals (synaptosomes) of the medial prefrontal cortex in rats with neuropathic pain. Pain155:377–87.
24.
IkedaRTakahashiYInoueKKatoF.2007. NMDA receptor-independent synaptic plasticity in the central amygdala in the rat model of neuropathic pain. Pain127:161–72.
25.
ImaiSSaekiMYanaseMHoriuchiHAbeMNaritaM, and others. 2011. Change in microRNAs associated with neuronal adaptive responses in the nucleus accumbens under neuropathic pain. J Neurosci31:15294–99.
26.
JiGFuYRuppertKANeugebauerV.2007. Pain-related anxiety-like behavior requires CRF1 receptors in the amygdala. Mol Pain3:13.
27.
JiGNeugebauerV.2011. Pain-related deactivation of medial prefrontal cortical neurons involves mGluR1 and GABA(A) receptors. J Neurophysiol106:2642–52.
28.
JiGNeugebauerV.2014. CB1 augments mGluR5 function in medial prefrontal cortical neurons to inhibit amygdala hyperactivity in an arthritis pain model. Eur J Neurosci39:455–66.
29.
JiGSunHFuYLiZPais-VieiraMGalhardoV, and others. 2010. Cognitive impairment in pain through amygdala-driven prefrontal cortical deactivation. J Neurosci30:5451–64.
30.
JiangHFangDKongLYJinZRCaiJKangXJ, and others. 2014. Sensitization of neurons in the central nucleus of the amygdala via the decreased GABAergic inhibition contributes to the development of neuropathic pain-related anxiety-like behaviors in rats. Mol Brain7:72.
31.
JohansenJPFieldsHLManningBH. 2001. The affective component of pain in rodents: direct evidence for a contribution of the anterior cingulate cortex. Proc Natl Acad Sci U S A98:8077–82.
32.
KalmanEKeayKA. 2014. Different patterns of morphological changes in the hippocampus and dentate gyrus accompany the differential expression of disability following nerve injury. J Anat225:591–603.
33.
KeayKAMonassiCRLevisonDBBandlerR.2004. Peripheral nerve injury evokes disabilities and sensory dysfunction in a subpopulation of rats: a closer model to human chronic neuropathic pain?Neurosci Lett361:188–91.
34.
KimHChenLLimGSungBWangSMcCabeMF, and others. 2012. Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression. J Clin Invest122:2940–54.
35.
LaBudaCJFuchsPN. 2005. Attenuation of negative pain affect produced by unilateral spinal nerve injury in the rat following anterior cingulate cortex activation. Neuroscience136:311–22.
36.
LaGraizeSCLaBudaCJRutledgeMAJacksonRLFuchsPN. 2004. Differential effect of anterior cingulate cortex lesion on mechanical hypersensitivity and escape/avoidance behavior in an animal model of neuropathic pain. Exp Neurol188:139–148.
37.
LauCNgLThompsonCPathakSKuanLJonesA, and others. 2008. Exploration and visualization of gene expression with neuroanatomy in the adult mouse brain. BMC Bioinformatics9:153.
38.
Leite-AlmeidaHAlmeida-TorresLMesquitaARPertovaaraASousaNCerqueiraJJ, and others. 2009. The impact of age on emotional and cognitive behaviours triggered by experimental neuropathy in rats. Pain144:57–65.
39.
Leite-AlmeidaHGuimarãesMRCerqueiraJJRibeiro-CostaNAnjos-MartinsHSousaN, and others. 2014. Asymmetric c-fos expression in the ventral orbital cortex is associated with impaired reversal learning in a right-sided neuropathy. Mol Pain10:41.
40.
LiXYWangNWangYJZuoZXKogaKLuoF, and others. 2014. Long-term temporal imprecision of information coding in the anterior cingulate cortex of mice with peripheral inflammation or nerve injury. J Neurosci34:10675–87.
41.
MartuscelloRTSpenglerRNBonoiuACDavidsonBAHelinskiJDingH, and others. 2012. Increasing TNF levels solely in the rat hippocampus produces persistent pain-like symptoms. Pain153:1871–82.
42.
Matsuzawa-YanagidaKNaritaMNakajimaMKuzumakiNNiikuraKNozakiH, and others. 2007. Usefulness of antidepressants for improving the neuropathic pain-like state and pain-induced anxiety through actions at different brain sites. Neuropsychopharmacology33:1952–65.
43.
MetzAEYauHJCentenoMVApkarianAVMartinaM.2009. Morphological and functional reorganization of rat medial prefrontal cortex in neuropathic pain. Proc Natl Acad Sci U S A106:2423–8.
44.
MutsoAARadzickiDBalikiMNHuangLBanisadrGCentenoMV, and others. 2012. Abnormalities in hippocampal functioning with persistent pain. J Neurosci32:5747–56.
45.
MyersBMeerveldBGV. 2010. Elevated corticosterone in the amygdala leads to persistent increases in anxiety-like behavior and pain sensitivity. Behav Brain Res214:465–9.
46.
NeugebauerVLiWDBirdGCBhaveGGereauRW. 2003. Synaptic plasticity in the amygdala in a model of arthritic pain: differential roles of metabotropic glutamate receptors 1 and 5. J Neurosci23:52–63.
47.
OhSWHarrisJANgLWinslowBCainNMihalasS, and others. 2014. A mesoscale connectome of the mouse brain. Nature508:207–14.
48.
Pais-VieiraMMendes-PintoMMLimaDGalhardoV.2009. Cognitive impairment of prefrontal-dependent decision-making in rats after the onset of chronic pain. Neuroscience161:671–9.
49.
PedersenLHScheel-KrügerJBlackburn-MunroG.2007. Amygdala GABA-A receptor involvement in mediating sensory-discriminative and affective-motivational pain responses in a rat model of peripheral nerve injury. Pain127:17–26.
50.
PenzoMARobertVLiB.2014. Fear conditioning potentiates synaptic transmission onto long-range projection neurons in the lateral subdivision of central amygdala. J Neurosci34:2432–7.
51.
QuCKingTOkunALaiJFieldsHLPorrecaF.2011. Lesion of the rostral anterior cingulate cortex eliminates the aversiveness of spontaneous neuropathic pain following partial or complete axotomy. Pain152:1641–8.
52.
RenWKiritoshiTGregoireSJiGGuerriniRCaloG, and others. 2013. Neuropeptide S: a novel regulator of pain-related amygdala plasticity and behaviors. J Neurophysiol110:1765–81.
53.
RenWJLiuYZhouLJLiWZhongYPangRP, and others. 2011. Peripheral nerve injury leads to working memory deficits and dysfunction of the hippocampus by upregulation of TNF-α in rodents. Neuropsychopharmacology36:979–92.
SantarelliLSaxeMGrossCSurgetABattagliaFDulawaS, and others. 2003. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science301:809.
56.
SawadaANiiyamaYAtakaKNagaishiKYamakageMFujimiyaM.2014. Suppression of bone marrow–derived microglia in the amygdala improves anxiety-like behavior induced by chronic partial sciatic nerve ligation in mice. Pain155:1762–72.
57.
SchwartzNTemkinPJuradoSLimBKHeifetsBDPolepalliJS, and others. 2014. Chronic pain. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens. Science345:535–42.
58.
SorgeREMartinLJIsbesterKASotocinalSGRosenSTuttleAH, and others. 2014. Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nat Methods11:629–32.
59.
SutoTEisenachJCHayashidaKI. 2014. Peripheral nerve injury and gabapentin, but not their combination, impair attentional behavior via direct effects on noradrenergic signaling in the brain. Pain155:1935–42.
60.
ThibaultKLinWKRancillacAFanMSnollaertsTSordoilletV, and others. 2014. BDNF-dependent plasticity induced by peripheral inflammation in the primary sensory and the cingulate cortex triggers cold allodynia and reveals a major role for endogenous BDNF as a tuner of the affective aspect of pain. J Neurosci34:14739–51.
61.
UhelskiMLDavisMAFuchsPN. 2012. Pain affect in the absence of pain sensation: evidence of asomaesthesia after somatosensory cortex lesions in the rat. Pain153:885–92.
62.
Ulrich-LaiYMXieWMeijJTADolgasCMYuLHermanJP. 2006. Limbic and HPA axis function in an animal model of chronic neuropathic pain. Physiol Behav88:67–76.
63.
WangGQCenCLiCCaoSWangNZhouZ, and others. 2015. Deactivation of excitatory neurons in the prelimbic cortex via Cdk5 promotes pain sensation and anxiety. Nat Commun6:7660.
64.
WuYNaXZangYCuiYXinWPangR, and others. 2014. Upregulation of tumor necrosis factor-alpha in nucleus accumbens attenuates morphine-induced rewarding in a neuropathic pain model. Biochem Biophys Res Commun449:502–7.
65.
YalcinIBohrenYWaltispergerESage-CioccaDYinJCFreund-MercierMJ, and others. 2011. A time-dependent history of mood disorders in a murine model of neuropathic pain. Biol Psychiatry70:946–53.
66.
ZhangZTaoWHouYYWangWLuYGPanZZ. 2014. Persistent pain facilitates response to morphine reward by downregulation of central amygdala GABAergic function. Neuropsychopharmacology. 39:2263–71.
