Chronic Pain-Related Cognitive Deficits: Preclinical Insights into Molecular, Cellular, and Circuit Mechanisms

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 2024 Mar 12

PMID 38470516

Authors

Siyi Han

Jie Wang

Wen Zhang

Xuebi Tian

Affiliations

Soon will be listed here.

Abstract

Cognitive impairment is a common comorbidity of chronic pain, significantly disrupting patients' quality of life. Despite this comorbidity being clinically recognized, the underlying neuropathological mechanisms remain unclear. Recent preclinical studies have focused on the fundamental mechanisms underlying the coexistence of chronic pain and cognitive decline. Pain chronification is accompanied by structural and functional changes in the neural substrate of cognition. Based on the developments in electrophysiology and optogenetics/chemogenetics, we summarized the relevant neural circuits involved in pain-induced cognitive impairment, as well as changes in connectivity and function in brain regions. We then present the cellular and molecular alternations related to pain-induced cognitive impairment in preclinical studies, mainly including modifications in neuronal excitability and structure, synaptic plasticity, glial cells and cytokines, neurotransmitters and other neurochemicals, and the gut-brain axis. Finally, we also discussed the potential treatment strategies and future research directions.

Citing Articles

Sleep Disorders: Pathogenesis and Therapeutic Interventions.

Liu C, He Z, Wu Y, Liu Y, Li Z, Jia Y MedComm (2020). 2025; 6(3):e70130.

PMID: 40066230 PMC: 11892028. DOI: 10.1002/mco2.70130.

CHOP-Mediated Disruption of Hippocampal Synaptic Plasticity and Neuronal Activity Contributes to Chronic Pain-Related Cognitive Deficits.

Meng Q, Su S, Lei L, Zhang Y, Duan J, Ren X CNS Neurosci Ther. 2025; 31(1):e70160.

PMID: 39817595 PMC: 11736631. DOI: 10.1111/cns.70160.

The involvement of the dysfunctional insulin receptor signaling system in long COVID patients with diabetes and chronic pain and its implications for the clinical management using taVNS.

Li R, Liu W, Liu D, Jin X, Wang S Front Pain Res (Lausanne). 2024; 5:1486851.

PMID: 39654800 PMC: 11625755. DOI: 10.3389/fpain.2024.1486851.

A Systematic Review on the Neuropsychological Assessment of Patients with LBP: The Impact of Chronic Pain on Quality of Life.

Anselmo A, Pagano M, Cappadona I, Cardile D, Russo F, Laudisio A J Clin Med. 2024; 13(20).

PMID: 39458099 PMC: 11508970. DOI: 10.3390/jcm13206149.

References

Phelps C, Navratilova E, Porreca F . Cognition in the Chronic Pain Experience: Preclinical Insights. Trends Cogn Sci. 2021; 25(5):365-376. PMC: 8035230. DOI: 10.1016/j.tics.2021.01.001. View

Treede R, Rief W, Barke A, Aziz Q, Bennett M, Benoliel R . A classification of chronic pain for ICD-11. Pain. 2015; 156(6):1003-1007. PMC: 4450869. DOI: 10.1097/j.pain.0000000000000160. View

Nahin R, DeKosky S . Comorbid Pain and Cognitive Impairment in a Nationally Representative Adult Population: Prevalence and Associations With Health Status, Health Care Utilization, and Satisfaction With Care. Clin J Pain. 2020; 36(10):725-739. PMC: 9396625. DOI: 10.1097/AJP.0000000000000863. View

Zhao W, Zhao L, Chang X, Lu X, Tu Y . Elevated dementia risk, cognitive decline, and hippocampal atrophy in multisite chronic pain. Proc Natl Acad Sci U S A. 2023; 120(9):e2215192120. PMC: 9992778. DOI: 10.1073/pnas.2215192120. View

Kazim M, Strahl A, Moritz S, Arlt S, Niemeier A . Chronic pain in osteoarthritis of the hip is associated with selective cognitive impairment. Arch Orthop Trauma Surg. 2022; 143(4):2189-2197. PMC: 10030427. DOI: 10.1007/s00402-022-04445-x. View

Corti E, Gasson N, Loftus A . Cognitive profile and mild cognitive impairment in people with chronic lower back pain. Brain Cogn. 2021; 151:105737. DOI: 10.1016/j.bandc.2021.105737. View

Cunha A, Pereira-Mendes J, Almeida A, Guimaraes M, Leite-Almeida H . Chronic pain impact on rodents' behavioral repertoire. Neurosci Biobehav Rev. 2020; 119:101-127. DOI: 10.1016/j.neubiorev.2020.09.022. View

Tracey I, Mantyh P . The cerebral signature for pain perception and its modulation. Neuron. 2007; 55(3):377-91. DOI: 10.1016/j.neuron.2007.07.012. View

McCarberg B, Peppin J . Pain Pathways and Nervous System Plasticity: Learning and Memory in Pain. Pain Med. 2019; 20(12):2421-2437. DOI: 10.1093/pm/pnz017. View

10.

Hashmi J, Baliki M, Huang L, Baria A, Torbey S, Hermann K . Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits. Brain. 2013; 136(Pt 9):2751-68. PMC: 3754458. DOI: 10.1093/brain/awt211. View

11.

Yang S, Chang M . Chronic Pain: Structural and Functional Changes in Brain Structures and Associated Negative Affective States. Int J Mol Sci. 2019; 20(13). PMC: 6650904. DOI: 10.3390/ijms20133130. View

12.

Moriarty O, McGuire B, Finn D . The effect of pain on cognitive function: a review of clinical and preclinical research. Prog Neurobiol. 2011; 93(3):385-404. DOI: 10.1016/j.pneurobio.2011.01.002. View

13.

You Z, Zhang S, Shen S, Yang J, Ding W, Yang L . Cognitive impairment in a rat model of neuropathic pain: role of hippocampal microtubule stability. Pain. 2018; 159(8):1518-1528. PMC: 6053326. DOI: 10.1097/j.pain.0000000000001233. View

14.

Hisaoka-Nakashima K, Ohata K, Yoshimoto N, Tokuda S, Yoshii N, Nakamura Y . High-mobility group box 1-mediated hippocampal microglial activation induces cognitive impairment in mice with neuropathic pain. Exp Neurol. 2022; 355:114146. DOI: 10.1016/j.expneurol.2022.114146. View

15.

Wang Y, Li C, Han R, Wang Z, Gao Y, Zhu X . PCC0208009, an indirect IDO1 inhibitor, alleviates neuropathic pain and co-morbidities by regulating synaptic plasticity of ACC and amygdala. Biochem Pharmacol. 2020; 177:113926. DOI: 10.1016/j.bcp.2020.113926. View

16.

Palazzo E, Romano R, Luongo L, Boccella S, De Gregorio D, Giordano M . MMPIP, an mGluR7-selective negative allosteric modulator, alleviates pain and normalizes affective and cognitive behavior in neuropathic mice. Pain. 2015; 156(6):1060-1073. DOI: 10.1097/j.pain.0000000000000150. View

17.

Boccella S, Marabese I, Iannotta M, Belardo C, Neugebauer V, Mazzitelli M . Metabotropic Glutamate Receptor 5 and 8 Modulate the Ameliorative Effect of Ultramicronized Palmitoylethanolamide on Cognitive Decline Associated with Neuropathic Pain. Int J Mol Sci. 2019; 20(7). PMC: 6480075. DOI: 10.3390/ijms20071757. View

18.

Boccella S, Cristiano C, Romano R, Iannotta M, Belardo C, Farina A . Ultra-micronized palmitoylethanolamide rescues the cognitive decline-associated loss of neural plasticity in the neuropathic mouse entorhinal cortex-dentate gyrus pathway. Neurobiol Dis. 2018; 121:106-119. DOI: 10.1016/j.nbd.2018.09.023. View

19.

Guida F, Luongo L, Marmo F, Romano R, Iannotta M, Napolitano F . Palmitoylethanolamide reduces pain-related behaviors and restores glutamatergic synapses homeostasis in the medial prefrontal cortex of neuropathic mice. Mol Brain. 2015; 8:47. PMC: 4532244. DOI: 10.1186/s13041-015-0139-5. View

20.

Tajerian M, Leu D, Zou Y, Sahbaie P, Li W, Khan H . Brain neuroplastic changes accompany anxiety and memory deficits in a model of complex regional pain syndrome. Anesthesiology. 2014; 121(4):852-65. PMC: 4175292. DOI: 10.1097/ALN.0000000000000403. View