Neurobiology of Pain
– An Introduction
Pain is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”
Because the preferred choice of treatment for pain is based at least in part on the type of pain, it is important to understand the different types of pain and how to distinguish one type from the other. The experience of pain is often a combination of different types and therefore the treatment of pain often benefits from the use of more than one approach and/or type of pain medication/treatment.
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Pain Perception and the Pain Experience
Brief Overview of the Pain Circuits
The first step in perceiving pain is the result of stimulation of “nociceptors,” special pain receptors located in the periphery of the body including skin, bone and other tissues . The nociceptors send signals to an area of the spinal cord called the dorsal horn. In turn, signals are than sent from the dorsal horn to the brain via neural circuits called the “ascending pathways” (See below for more about the ascending pathways). When the brain receives these signals, additional processing occurs in higher brain centers allowing conscious awareness and emotional response to the painful stimulus.
Nociceptors are specialized sensory nerves that are responsive to damaging or potentially damaging stimuli including temperature, mechanical, chemical stimuli as well as others that have variable functions. They are found in any area of the body that can sense noxious stimuli either externally or internally. The cell bodies of these nociceptors neurons are located in either the dorsal root ganglia (DRG) in the spinal cord or the trigeminal ganglia that serve the face and head. The DRG is a site in the spinal cord where pain signalling is modified by other nerves and a site where naturally occuring opioids, the enkephalins and endomorphins, act to influence pain perception. The DRG is also thought to be a contributing site for the evolution of central sensitization.
Nociceptors send signals to the spinal cord and, via the ascending spinal pathways, to the brain in a process called “nociception” resulting in the conscious perception of pain. The nociceptors are a site of action for topical pain medications including capsaicin, ketamine, anesthetics and other drugs.
Ascending Spinal Pathways
From the spinal cord, pain signals are transmitted via the ascending spinal pathways to portions of the brain that are responsible for processing the sensory components of pain. These parts of the brain include the thalamus and midbrain with corresponding projections to limbic regions of the brain that are involved in processing pain signals to generate the perceived elements of pain including emotion and memory. Pain signals are processed consciously and unconsciously.
In Detail –
Secondary order neurons arising in the spinal cord transmit nociceptive input to the thalamus through ascending pathways such as the spinothalamic tract, which functions as a relay station to higher cortical centers.
These centers include:
The anterior cingulate cortex:
Involved in anxiety, anticipation of pain, attention to pain, and motor responses
The insular cortex:
Which may play a role in the sensory discriminative and aective aspects of pain that contribute to the negative emotional responses and behaviors associated with painful stimuli.
The prefrontal cortex:
Which is important for sensory integration, decision making, memory retrieval, and attention processing in relation to pain.
The primary and secondary somatosensory cortices:
that localize and interpret noxious stimuli.
The nucleus accumbens:
which is involved in placebo analgesia and is the primary center for pleasure and the sense of well-being.
The amygdala, hippocampus, and other parts of the limbic system:
Which are involved in the formation and storage of memories associated with emotional events, aect, arousal, and attention to pain and learning. The limbic system may also be partially responsible for the fear that accompanies pain.
The final experience of pain is a result of modifications by various centers in the brain that communicate together, by emotion and personal experience, by genetics – all of which are referred to as the “Neuromatrix,” which make their final impact on the higher, cortical areas of the brain that reflect the actual conscious experience of pain.
The neuromatrix theory of pain provides a new conceptual framework to understand pain. It proposes “that the output patterns of the body-self neuromatrix activate perceptual, homeostatic, and behavioral programs after injury, pathology, or chronic stress. Pain, then, is produced by the output of a widely distributed neural network in the brain rather than limited to sensory input evoked by injury, inflammation, or other pathology. The neuromatrix, which is genetically determined and modified by sensory experience, is the primary mechanism that generates the neural pattern that produces pain.” The final pain pattern is determined by multiple influences, of which the body’s sensory input is only a part, that converge on the neuromatrix.
Thus, the pain experience is a function of signals triggered by peripheral receptors that travel to the spinal cord, then to the brain and then back to the spinal cord. The experience of pain can be modified by emotional reactions and other brain processing that affects the function of any of these components in the pain processing system as well as by medications interacting on any of these components.
After processing pain signals, the brain then sends signals back to the dorsal horn of the spinal cord via the “descending pathways.” which for the most part are inhibitory, meaning they act to diminish the perceived severity of the pain experience (See below for more about the descending pathways).
The descending pathways send signals from the brain to the spinal cord that inhibit pain (dorsal horn and DRG of the spinal cord via the rostral ventromedial medulla and the periaqueductal grey (PAG) of the midbrain). In the dorsal horn of the spinal cord, serotonin, noradrenaline (norepinephrine) and other neurotransmitters are released then bind to nerves in the spinal cord. These nerves regulate the influx and transmission of pain signals, allowing for increasing or, usually, decreasing pain signals. As a neurotransmitter, serotonin sometimes increases pain and sometimes inhibits pain, depending on the nerve pathway. Noradrenaline is mostly inhibitory to pain. The antidepressant medications such as Cymbalta, Effexor and Savella as well as some opioids (tramadol, tapentadol, buprenorphine and levorphanol) work on these pathway by inhibiting the reuptake of serotonin and noradrenaline that results in enhancing their inhibition of pain. It appears that it is the noradrenaline that plays the greatest role in inhibiting pain, especially nerve pain.
Since painful stimuli that are processed by the brain can result in either suppression or increased pain, we look to modify these pathways as one means of treating pain. As noted above, some medications work on these pathways. Sometimes supplements can also affect these pathways, including those that inhibit COMT, an enzyme that metabolizes norardrenaline for example (see nutrition and supplements). It is believed that the pain benefits obtained with mindful exercises such as meditation, prayer, hypnosis, deep relaxation exercises etc. are brought about by increasing these inhibitory signals via the descending pathways. In some cases however, the brain prcessing may result in increased severity of pain such as what may occur when an emotional reaction to pain makes the pain feel worse.
Nociceptive pain is caused by activation of neural pathways in response to damaging or potentially damaging stimuli to body tissue such as occurs with chemical or mechanical trauma or burns. It is usually described as a sharp, aching, or throbbing pain. Nociceptive pain is further divided into “visceral” pain, originating from the organs inside the body, and “somatic” pain, originating from muscles, bone and skin. Visceral pain is often vague, difficult to describe and hard to localize. Nocicptive pain is usually a symptom of a disease process.
“Neuropathic” or nerve pain is pain initiated or caused by a primary lesion or dysfunction in a nerve or in the nervous system or pain arising as a direct consequence of a lesion or disease affecting the nervous system. Nerve pain is usually perceived as burning, electric, shock-like, tingling or sharp and may start at one location and shoot, or “radiate” to another location (like sciatica). Neuropathic pain can be “peripheral,” (outside the central nervous system),” like carpal tunnel pain or “central,” originating in the spinal cord or brain. Neuropathic pain is often a disease process, not simply the symptom of one.
For more information: Assessment and Management of Neuropathic Pain
Hyperalgesia is an exaggerated, increased painful response to a stimulus which is normally painful and is classified as either primary or secondary. Primary hyperalgesia accompanies injury to tissue as an outcome of peripheral nociceptor sensitization. In contrast, secondary hyperalgesia is found in the neighboring intact tissue because of the sensitization of the central nervous system. It is thought that this sensation can be attributed to either the extension of the receptive fields of damaged nerves, or by transmission of excitatory signals that spread through neighboring uninjured nerve fibers.
Allodynia is a term that describes the experience of pain arising from a stimulus which does not normally provoke pain. This pain can stem from undamaged neighboring fibers, the dorsal root ganglion in the spinal cord, or along other points of the damaged nerve. Allodynia may result from reduced nerve thresholds and is usuallly characterized as either thermal or mechanical in nature. Allodynia is a common symptom associated with fibromyalgia and migraine headaches but may arise as a result of other chronic painful conditions possibly related to central sensitization.
For more information: Assessment and Management of Central Sensitization
Central Sensitization is a process of hyper-responsiveness to sensory stimuli which is a result of chronic pain-induced changes in the spinal cord and brain. It can be an important contributing process to the chronic pain experience.
For more information: Assessment and Management of Central Sensitization
Receptors and Neurotransmitters
Receptors are cellular structures, usually a complex protein molecule found on the surface of a cell, that interacts or binds with a chemical which then triggers a response. These chemicals may be neurotransmitters (in the nervous system), hormones or drugs. A chemical or drug that triggers a reaction with a receptor is referred to as an “agonist,” while one that blocks the activity of a receptor is referred to as an “antagonist.”
In the world of pain, there are a handful of well-studied receptors that play prominent roles, most notably the opioid receptors which interact with both endogenous opioids (opioids manufactured by the body) and exogenous opioids (opioid medications). Opioid receptors are distributed widely in the brain and spinal cord, particularly in areas of the nervous system associated with pain perception and transmission. Opioid receptors are also found in the digestive tract where they play a key role in how opioid medications can cause constipation.
Besides the opioid receptors, another receptor that plays a significant roles in pain, especially nerve pain, is the NMDA receptor. It remains uncertain how NMDA and opioid receptors interact but blocking the NMDA receptor appears to reduce the development of opioid tolerance and opioid induced hyperalgesia. The list of receptors important in pain is not limited to only these few receptors but these are the receptors that when understood can provide insights towards better choices for treating pain. Thus, understanding the nature of a person’s pain and understanding the difference in how medications work allows for tailoring an individualized pain management plan to optimize pain control. (For more information about opioid and NMDA receptors, see Neurobiology of Opioids).
Sensitization and stimulation of nociceptors, both of which can be caused by numerous factors, effectively lower neuronal thresholds of action potentials and promote peripheral sensitization. These factors include inflammatory mediators that are discharged from nociceptive terminals, including substance P and the calcitonin gene-related peptide. These mediators promote vascular permeability, which causes local edema and the leakage of growth factors, prostaglandins, cytokines, and bradykinin. It is thought that the multifactorial dependence of various substances on producing nociceptive sensitization may explain why there is no single comprehensively effective drug.
The Distinction between Nociceptive and Neuropathic Pain
Neuroscientists use distinct pain models for nocicptive (non-neuropathic) pain and neuropathic pain because of different proposed mechanisms, different experiential perceptions and, most importantly, to guide effective treatment options. In many ways making this distinction offers advantages to the management of chronic pain. That being said, the actual distinction between these two categories of pain are blurred.
The same neurotransmitters, neuropeptides, cytokines, and enzymes are implicated in both types of pain, with a large degree of overlap. Opioids are effective for both types of pain, though less so for neuropathic pain often requiring higher doses than for nociceptive pain. NMDA receptor antagonists (ketamine, and others) are often considered to be effective for neuropathic pain only, being intricately involved in the process of central sensitization, but preclinical and clinical studies have shown that they reduce nociceptive pain also.
It is important to note also that ascending spinal pathways, supraspinal regions that process these signals, and descending modulation pathways are essentially the same for neuropathic and nociceptive pain. All of the ways that pain signalling can be modified at any of these areas will affect both neuropathic and nociceptive pain. The rest of the neuromatrix of the pain experience, including brain reorganization and emotional interplay are also shared between both neuropathic and nociceptive pain.
In conclusion, although treatment based on the mechanism(s) of pain is widely accepted to be theoretically better than treatment based on the cause of pain, or empirical treatment, this paradigm of neuropathic vs. nociceptive pain should encourage flexibility in pain management as implemented in clinical practice.
New Frontiers in the Understanding of Chronic Pain
Two arenas of recent scientific study of pain are evolving in ways that promise to revolutionize both our understanding and our treatment of chronic pain. These fields of study are neuroinflammation including the role of glial cells and the field of epigenetics.
Neuroinflammation and Glial Cells
Glial cells are cells found in the central and peripheral nervous system. They function to maintain balance in nerve and neurotransmitter activity, they form myelin (the coating of some nerve cells), and provide support and protection for neurons (nerve cells). Glial cells are derived from the immune system, the most common of which are microglia cells and astrocytes. Glia cells provide a supportive matrix for nerve cells, supplying nutrients and oxygen and aid in the repair of damaged cells. However, when activated, glial cells also are important in the evolution and maintenance of chronic nerve pain through the release of peptides known as cytokines that are pro-inflammatory, triggering chronic pain. They may play a role in opioid function including opioid-induced hyperalgesia and opioid tolerance. It is believed that pathologic glial cell activation plays a significant role in the evolution of fibromyalgia pain, central sensitization and other chronic pain syndromes.
Early studies suggest that medications or supplements that inhibit glial activation may reduce the development of chronic nerve pain or reduce the severity of existing nerve pain. They may also be useful in suppressing the development of opioid tolerance. Various inhibitors of glial activation that are being evaluated for clinical use in the managment of chronic pain include minocycline, a tetracycline-class antibiotic, low dose naltrexone, palmitoylethanolamide (PEA) and Acetyl-L-carnitine. There is some evidence as well that gabapentin may inhibit glial cell activation as another mechanism of action responsible for its effectiveness in treating nerve pain. Furthermore, there may be a role for antioxidants and NRF2 activators as well in the management of chronic nerve pain related to glial cell activation.
Over the last few decades our knowledge of genetics and the structure of DNA has dramatically advanced our knowledge in the field of health. Mapping the human genome probably represents the greatest scientific achievement of our lifetime with the promise to impact our understanding of health-related topics in ways never possible before. How genes get turned on or off, what makes them active or not and the nature of these processes are what make up the field of epigenetics. Within the broader field of epigenetics lies the field of neuroepigenetics that represents the study of the nervous system, the brain, nerve cells and that includes the study of pain.
In the scientific community, a long standing debate has persisted regarding the role of “nature vs. nurture,” or is some cause and effect due to genetic or environmental influence – or both. It is now understood that these two elements are intimately intertwined so that environmental influences can impact the function of DNA and genes, and this impact can not only become permanent but can be passed on from one generation to the next. The implication of this is huge and has already triggered an incredible amount of research in this field of epigenetics. While this field of study is in its infancy, it is beginning to impact what we know about pain, the evolution from acute to chronic pain, the effects of chronic pain on the nervous system as well as new ideas how to manage pain.
This topic will be explored further in the near future. See below for references.
- Introduction to Pain Pathways and Mechanisms
- Pain and the Neuromatrix in the Brain 2001
- Neuropathic pain – mechanisms and their clinical implications – 2014
Pain – Epigenetics
Pain – Epigenetics, Acute Pain Transition to Chronic Pain
Pain – Epigenetics, Opioids
Pain – Neuroinflammation and Glial Cells
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