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Marcin Karcz,1 Alaa Abd-Elsayed,2 Krishnan Chakravarthy,3 Aman Mansoor,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 Vinny Francio,22 Dawood Syed,7 Timothy Deer1 1The Spine and Nerve Centers of the Virginias, Charleston, WV, USA; 2Department of Anesthesiology, University of Wisconsin, Madison, WI, USA; 3Innovative Pain Treatment Solutions, San Diego, CA, USA; 4Aurora Pain Management, Aurora Health Care, Oshkosh, WI, USA; 5Anesthesiology and Perioperative Medicine, Mayo Clinic, Phoenix, AZ, USA; 6Department of Anesthesiology, Ohio Health System, Columbus, OH, USA; 7Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS, USA; 8Department of Pain Medicine, Northshore University Health System, Skokie, IL, USA; 9Department of Anesthesiology and Pain Medicine, Rush University Medical Center, Oak Park, IL, USA; 10Department of Pain Management, Insight Institute of Neurosurgery & Neuroscience, Flint, MI, USA; 11Pain Institute of Southern Arizona, Tucson, AZ, USA; 12Mays and Schnapp Neurospine and Pain, Memphis, TN, USA; 13Department of Pain Management, Erie County Medical Center, Buffalo, NY, USA; 14Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA; 15Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 16Department of Physical Medicine & Rehabilitation, Larkin Hospital Health System, Miami, FL, USA; 17Department of Pain Management at Northern Light Health – Eastern Maine Medical Center, Bangor, ME, USA; 18Department of Pain Medicine, University of California Davis Health System, Sacramento, CA, USA; 19Department of Physical Medicine & Rehabilitation, Montefiore Medical Center, Bronx, NY, USA; 20Department of Physical Medicine & Rehabilitation, Michigan State University, Lansing, MI, USA; 21Department of Anesthesiology and Perioperative Medicine, Rutgers Robert Wood Johnson, New Brunswick, NJ, USA; 22Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, USACorrespondence: Marcin Karcz, The Spine and Nerve Centers of the Virginias, Charleston, WV, USA, Email drmarcinkarcz@gmail.comAbstract: 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, nociceptive pain, neuropathic pain, nociplastic pain, physiological effects, pain pathways, sensitization