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Review
. 2024 Nov 16:17:3757-3790.
doi: 10.2147/JPR.S475351. eCollection 2024.

Pathophysiology of Pain and Mechanisms of Neuromodulation: A Narrative Review (A Neuron Project)

Marcin Karcz  1 , Alaa Abd-Elsayed  2 , Krishnan Chakravarthy  3 , Mansoor M Aman  4 , Natalie Strand  5 , Mark N Malinowski  6 , Usman Latif  7 , David Dickerson  8 , Tolga Suvar  9 , Timothy Lubenow  9 , Evan Peskin  10 , Ryan D'Souza  5 , Eric Cornidez  11 , Andrew Dudas  12 , Christopher Lam  7 , Michael Farrell Ii  13 , Geum Yeon Sim  14 , Mohamad Sebai  15 , Rosa Garcia  16 , Lucas Bracero  1 , Yussr Ibrahim  17 , Syed Jafar Mahmood  18 , Marco Lawandy  19 , Daniel Jimenez  20 , Leili Shahgholi  15 , Kamil Sochacki  21 , Mohamed Ehab Ramadan  15 , Vinicius Tieppo Francio  22 , Dawood Sayed  7 , Timothy Deer  1
Affiliations
Review

Pathophysiology of Pain and Mechanisms of Neuromodulation: A Narrative Review (A Neuron Project)

Marcin Karcz et al. J Pain Res. .

Abstract

Pain serves as a vital innate defense mechanism that can significantly impact an individual's quality of life. Understanding the physiological effects of pain well plays an important role in developing novel pain treatments. Nociceptor neurons play a key role in pain and inflammation. Interactions between nociceptors and the immune system occur both at the site of injury and within the central nervous system. Modulating chemical mediators and nociceptor activity offers promising new approaches to pain management. Essentially, the sensory nervous system is essential for modulating the body's protective response, making it critical to understand these interactions to discover new pain treatment strategies. New innovations in neuromodulation have led to alternatives to opioids individuals with chronic pain with consequent improvement in disease-based treatment and nerve targeting. New neural targets from cellular and structural perspectives have revolutionized the field of neuromodulation. This narrative review aims to elucidate the mechanisms of pain transmission and processing, examine the characteristics and properties of nociceptors, and explore how the immune system influences pain perception. It further provides an updated overview of the physiology of pain and neuromodulatory mechanisms essential for managing acute and chronic pain. We assess the current understanding of different pain types, focusing on key molecules involved in each type and their physiological effects. Additionally, we compare painful and painless neuropathies and discuss the neuroimmune interactions involved in pain manifestation.

Keywords: neurons; neuropathic pain; nociceptive pain; nociplastic pain; pain pathways; physiological effects; sensitization.

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Conflict of interest statement

Dr Alaa Abd-Elsayed is a consultant for Medtronic and Curonix. Dr Mansoor M Aman is a consultant for Abbott and Medtronic. Dr Mark Malinowski reports personal fees from Abbott, Biotronik NEURO, SI Bone, Inc, Medtronic, and Nalu Medical. Dr Usman Latif reports grants and/or personal fees from Nalu Medical, SPR, Abbott, Nevro, Vertos, Spinal Simplicity, Omnia Medical, Brixton Biosciences, InFormed Consent, and Mainstay Medical, outside the submitted work. Dr David Dickerson reports grants and/or personal fees from Abbott, SPR, Biotronik, Vertos, and Vertex, outside the submitted work. Dr Timothy Lubenow reports grants and/or personal fees from Abbott, Boston Scientific, Pen Tec, PainTeq, Biotronik. Dr Michael Farrell II reports personal fees from Abbott, outside the submitted work. Dr Dawood Sayed reports personal fees and options from Painteq; personal fees from Saluda and Abbott; options from Mainstay and Surgentec, outside the submitted work. Dr Timothy Deer reports personal fees for consultancy and research from Abbott and Saluda, during the conduct of the study; personal fees for consultancy or research from Vertos, SpineThera, Mainstay, Cornerloc, Boston Scientific, PainTeq, Spinal Simplicity, SPR Therapeutics, Biotronik, Aurora, and Nervonic, outside the submitted work. In addition, Dr Timothy Deer has a patent pending to Abbott. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Route of pain transmission.
Figure 2
Figure 2
Rexed laminae.
Figure 3
Figure 3
Presynaptic and postsynaptic neurotransmitters and their receptors.
Figure 4
Figure 4
Complex pain pathways: stimulation of nociceptive nerve endings from joints, muscles/tendons, and skin are transmitted from the periphery to the spinal cord to the cortex in a complex pathway involving transduction, transmission, and modulation of the pain signal.
See this image and copyright information in PMC

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