Pain is an unpleasant sensory or emotional experience, but the ability to feel pain is an adaptive trait that can help organisms respond to threatening stimuli. There are objective, sensory aspects of pain (called nociception), as well as subjective, emotional and psychological elements of perceiving pain. Understanding both is key to defining pain physiology and providing effective analgesia to patients who are experiencing pain [1]. 

For the brain to be alerted to bodily pain, pain receptors (nociceptors) must produce electrical signals, a process known as transduction. There are numerous types of nociceptors both on the skin and within internal parts of the body, such as the muscles and bones, which are primed to detect mechanical damages, inflammation, or different levels of heat or cold. These signals can be propagated through the peripheral nervous system and central nervous system via the spinal cord (a process called transmission) and processed in the brain. There are two major pain “highways” that result in different experiences of pain. Myelinated A-delta nerve fibers transmit pain signals much more quickly, and produce sensations of sudden, sharp, localized pain. In contrast, unmyelinated C fibers transmit pain more slowly, and produce dull, diffuse, aching pains that often follow initial sharp pains [2]. 

The spinothalamic tract, which transmits nociceptive signals to the thalamus, brings about the conscious sensation of pain — a process separate from the purely sensory process of nociception. After the brain has received a pain signal, it can block or alter the intensity of pain signals depending on the circumstance (a process called modulation). The cerebral cortex and spinothalamic tract pass signals to the interneurons that connect the primary afferent neurons (from the nociceptors) and the secondary afferent neurons, and these modulatory signals influence neurotransmitter release during signal transmission [2]. Nociceptive signals are also relayed to brainstem, midbrain, and medulla, which can impact modulation. Within the brain, the experience of pain is created and shaped by past experiences, context, and emotional input. Thus, sensory (nociceptive) input is not required for the perception of pain, and a painful experience can be elicited by brain stimulation directly [3]. 

The body can become increasingly sensitized to pain. Inflammatory molecules such as histamine and prostaglandins can temporarily increase the excitability of nociceptors, which can be an adaptive mechanism to ensure the pain is addressed. Maladaptive sensitization conditions can also arise, however, when nociceptive receptors spontaneously react more to nonpainful stimuli, a process called hyperalgesia that can develop as part of other pathologies like rheumatoid arthritis [4]. 

Blocking the molecules that cause sensitization to pain is one approach toward treating pain. Drugs like aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs (NSAID) inhibit the synthesis of the prostaglandins, thereby slowing or stopping inflammation and reducing pain. Head pain, such as migraine, is one of the leading causes of morbidity worldwide, but most medications provide only partial relief. Scientists are studying the individual cells and genes that may be implicated in the physiology of head pain to target analgesia more precisely. One recent study created an “atlas” of the genes that are expressed in all of the cells of the key relay center for migraine and facial pain (the trigeminal ganglion) which could help researchers target the causes of a variety of forms of pain, from tooth pain to cluster headaches, more directly [5]. 

Beyond this research, which requires complex tissue-harvesting procedures to extract and genetically sequence the trigeminal ganglion, researchers are using non-invasive brain imaging technologies to better understand the underlying physiology of chronic pain and improve analgesia. Fibromyalgia, chronic pelvic pain, chronic low back pain, and various pain syndromes have been associated with differences in white matter integrity and gray matter density, gray matter volume and cortical thickness. Functional magnetic resonance imaging studies have collectively shown how the brain changes dramatically with chronic pain, with heightened responsivity to afferent stimuli, both harmful and non-harmful. By studying the brain’s default mode network (the parts of the brain active in a resting-state), researchers better understand how the brain is altered under conditions of chronic pain [3].  

As studies of pain perception after limb amputations have shown, sensory processing is quite plastic, and mediated by ever-shifting, extensive, and interconnected neural networks [3]. While this fact elucidates the complex nature of pain management, it also provides opportunities for adaptively altering the nervous system to reduce pain. 

References 

1. Venugopal K, Swamy M. Physiology of Pain. World Federation of Societies of Anesthesiologists. Published December 2, 2005. https://resources.wfsahq.org/atotw/physiology-of-pain/ 

2. Kendroud S, Fitzgerald LA, Murray I, Hanna A. Physiology, Nociceptive Pathways. StatPearls. September 28, 2021. https://www.ncbi.nlm.nih.gov/books/NBK470255/  

3. Martucci KT, Mackey SC. Neuroimaging of pain: Human evidence and clinical relevance of central nervous system processes and modulation. Anesthesiology. 2018;128(6):1241-1254. doi:10.1097/ALN.0000000000002137 

4. Kyranou M, Puntillo K. The transition from acute to chronic pain: might intensive care unit patients be at risk? Ann Intensive Care. 2012;2(1):36. doi:10.1186/2110-5820-2-36 

5. Yang L, Xu M, Bhuiyan SA, et al. Human and mouse trigeminal ganglia cell atlas implicates multiple cell types in migraine. Neuron. 2022;0(0). doi:10.1016/j.neuron.2022.03.003 

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