Introduction

Pain is likely the most common symptomatic complaint in medicine; an understanding of its pathophysiology is critical to interpreting it in patients.[1][2]

Differentiating between the terms nociception and pain is worthwhile. Nociception refers to the detection of noxious stimuli by nociceptors, followed by transduction and transmission of the sensory nervous information from the periphery to the brain. In comparison, pain refers to the product of higher brain center processing; it entails the actual unpleasant emotional and sensory experience generated from nervous signals. Reports of pain are thus not merely a direct output of nociception, they involve interaction with numerous inputs (attention, affective dimensions, autonomic variables, immune variables and more), and may be considered more accurately from the perspective of a neuromatrix.[2]

Cellular Level

When thermal, mechanical, or chemical stimuli reach a noxious intensity suggestive of injury, they become detected by nociceptors, which are a subpopulation of peripheral nerve fibers found in the skin, joints, viscera, bone, and muscle.[3]

The damaged tissue releases and produces numerous factors which in turn activate nerve endings. These factors include globulin, protein kinases, arachidonic acid, histamine, nerve growth factor (NGF), substance P (SP), calcitonin gene-related peptide (CGRP), among others. These factors stimulate transducer channels, with transient receptor potential (TRP) channels being the primary example.[3] TRP channels function similarly to voltage-gated potassium channel or nucleotide-gated channels and thus help to initiate receptor potentials, consequently inducing an action potential in the nerve fibers.[3][4][5]

The two major classes of nociceptors include medium diameter myelinated (A-delta) afferents which convey an acute, well-localized fast pain and small diameter unmyelinated “C” fibers that convey a poorly localized, slow pain.[3][4][5]

Based on electrophysiological studies, A-delta nociceptors may be further subdivided into Type I and Type II A-delta classes. Type I A-delta nociceptors function to respond to mechanical and chemical stimuli but generally detect heat only at higher thresholds (over 50 degrees C). By contrast, Type II A-delta nociceptors have a much greater sensitivity to heat but possess a very high mechanical threshold. Thus, in situations of direct mechanical stimuli (e.g., pinprick), Type I A-delta nociceptors are provoked first, whereas, in instances of acute noxious heat, the activity of Type II A-delta nociceptors are likely first triggered.[3][4][5]

Similar to the A-delta nociceptors, most unmyelinated C fibers are polymodal and thus respond to both mechanical and thermal noxious stimuli. Silent nociceptors also fall under this class of nociceptors. These afferents respond more sensitively to chemical stimuli (e.g., capsaicin and histamine) but are mechanically unresponsive unless preceded by tissue injury.[3][4][5]

Development

Due to the clear limitations of obtaining a direct measure of pain in fetuses, elucidating the timeline of the development of pain perception relies on secondary measures. During fetal development, nociception processes (the sensory receptors and spinal cord synapses) develop sooner than the thalamocortical pathway needed to produce a conscious perception of pain. Free nerve endings begin development at roughly seven weeks gestation, during a period where the laminar structure of the thalamus or cortex has yet to mature. Histological studies of human fetuses suggest that thalamic projections into the cortical plate typically develop around 23 to 30 week’s gestation age.[6] The typical hormonal stress responses to pain are observed in fetuses around 18 weeks gestation, while brain hemodynamic responses and behavioral reactions to nociceptive stimuli coincide by 26 weeks gestation. These observations support the general estimate that experience of pain takes place around 26 weeks gestation.[7][8]

Organ Systems Involved

While this article has noted that nociceptors are present in the viscera, skin, joints, bone, and muscle, an important consideration is that there are no nociceptors found in the CNS; this is the rationale for why awake craniotomy is possible, and not painful for the patient.

It is also necessary to appreciate that the specific sensory modalities leading to nociception differ depending on the type of tissue:

• In skin, noxious stimuli are commonly thermal, mechanical (e.g., a cut), and chemical (e.g., exogenous allergens)
• In the joints, noxious stimuli commonly derive from mechanical stress (e.g., excessive joint torque) and chemical inflammation
• In the visceral organs: mechanical distension, traction as well as chemical irritants are usually responsible for nociceptive signals
• In the muscles, strenuous mechanical exertion (e.g., blunt force, over-stretching) and chemical modalities are most common

Nociceptive signal transduction to the brain is what elicits the perception of pain. The complex biopsychosocial phenomenon of pain occurs in the cortical and subcortical regions, such as the thalamus, amygdala, hypothalamus, periaqueductal grey, basal ganglia and areas of the cerebral cortex. While in typical situations, nociception does typically precede perception of pain, there are clinical circumstances in which these interfaces do not overlap. Nociception can occur without subsequent awareness of pain, and pain can be present without a measurable underlying noxious stimulus. For instance, the former may be observable following severe trauma when victims are remarkably pain-free despite massive injury; the latter may be observable with individuals suffering from functional pain syndromes who report substantial pain without signs of physical damage.[9]

Function

The neural mechanisms for pain and nociception serve an adaptive function in minimizing tissue damage from the environment.  It is important to note that there are several operational categories of pain behavior. Withdrawal as a simple reflex action most commonly associates with acute pain of injury; spinal reflexes elicit these actions upon nociceptor activation. However, more complex behaviors are also intimately related to neural pain pathways. For instance, arm movements elicited in anticipation of an aversive stimulus to the eyes require the integration of reflex actions with higher-order spatial, sensory, and temporal information.[10][11]

Mechanism

Through the actions of numerous inflammatory mediators (as described earlier in this article), an “inflammatory soup” is secreted at the site of injury to stimulate nociceptor activation. Afferent nociceptors from the periphery transmit noxious signals to projection neurons located in the dorsal horn of the spinal cord. Cells in the dorsal horn are in layers of physiologically distinct sections called laminae.  Based on the type of synapse in the laminae formed by the nociceptive fiber, a subset of these projection neurons will relay information to the somatosensory cortex via the thalamus, which provides information regarding the spatial features and intensity of the painful stimulus.[3][4][5]

Given the distinction between pain and nociception, it is also essential to consider various neural pathways involved in the affective, cortical component of the pain experience. This process is facilitated by projection neurons which engage the cingulate and insular cortices through connections with the parabrachial nucleus of the brainstem as well as with the amygdala and is considered as the ascending pathway which initiates the conscious perception of pain. The ascending information may also prompt neurons of the rostral ventral medulla and midbrain periaqueductal gray to engage descending feedback systems that regulate the output from the spinal cord, and thus modulate pain sensation. This occurs via the release of hormones and chemicals (e.g., endogenous opioids, GABA, glycine) that can have analgesic properties to limit pain sensation. Conversely, substances such as substance P, glutamate, and aspartate may act on the spinal cord to excite the perception of pain.[3][4][5]

Local stimulation of A-delta and A-beta also serves to modulate transmission of pain information via excitation of interneurons. These interneurons serve an inhibitory effect on dorsal horn projection neurons which signal to the anterolateral system. This is the primary mechanism behind rubbing a wound in an effort to dull the sharp pain.[12]

There are a number of psychological processes behind pain perception. Attentional orienting to the painful sensation and its source can serve to heighten the painful experience. For instance, patients with somatic preoccupation and hypochondriasis are found to over-attend to bodily sensations, amplifying them as pain. Similarly, other factors such as cognitive appraisal of the meaning of the sensation, the emotional and psychophysiological reactions, expectations, and coping skills can all serve as feedback to influence pain perception.[13] 

Related Testing

The complex, multi-faceted and subjective nature of pain makes it rather challenging to measure clinically. Over the past few decades, a number of validated measures have undergone development in an effort to assist research on the mechanisms of pain and outcomes of measurement. For acute pain, relevant in the management of surgical procedures or acute mental illness, the visual analogue scale (VAS) and numeric rating scale (NRS) are most frequently used to assess the intensity of pain. For chronic pain, multidimensional tools such as the McGill Pain Questionnaire (MPQ) and the Brief Pain Inventory (BPI) have been developed.[14][15]

Currently, the tools as mentioned above are used mainly in the research setting, though new experimental measures of pain, for instance, neuroimaging as an objective measurement, are being proposed.[16]

Clinical Significance

The characteristics of a patient’s pain offer indications regarding its pathogenesis. A brief explanation of classes of pain is thus useful clinically to assist in the management of pain as a symptom and possible diagnosis of the underlying condition.

• Acute pain: At the site of local tissue injury, the activation of nociceptive transducers contributes to this form of pain. The local injury environment may further alter the characteristics of nociceptors, central connections, and the autonomic nervous system.[1][2][3][4]
• Chronic pain: Persistent pain is frequently related to conditions (e.g., diabetes mellitus, arthritis, and tumor growth) which potentiates chronic tissue inflammation or alteration of the properties of peripheral nerves (neuropathic). Given the unrelenting nature of chronic pain, expectations are that external factors such as stress, emotions, and the environment may produce a summative effect with the damaged tissue to enhance the intensity and persistence of the pain. [1-4]
• Somatic pain: This form of pain may be acute or chronic and is pain activated by the nociceptors in the cutaneous or deep tissues. In the case of cutaneous somatic pain, for instance, in the case of a skin cut, it is described as sharp or burning and is well localized. In the case of somatic pain arising from the deep tissues, such as in the joints, tendons, and bones, it is described as more throbbing or aching and is less localized.[1][2][3][4][17]
• Visceral pain: This pain arises mainly from the viscera and deep somatic structures (e.g., pain from the gastrointestinal tract). Visceral pain that is not distinctly localized is carried by the C fibers from the deep structures to the spinal cord.[17]
• Neuropathic: This persistent pain is often a consequence of damage to these nerve fibers, leading to increased spontaneous firing or alterations in their conduction or neurotransmitter properties.[16]
• Allodynia: Pain resulting from a typically harmless stimulus is referred to as allodynia. Though the mechanism is not fully understood, it is thought to potentially arise from 1) sensitization of the skin, leading to a decreased threshold of silent nociceptors or 2) damage to peripheral neurons inducing structural changes leading touch-sensitive fibers to reroute and form synapses in areas of the spinal cord that normally receive pain input.[3]
• Hyperalgesia: Occurs when noxious stimuli generate an exaggerated pain response. Similar mechanisms as proposed in the case of allodynia, with patients demonstrating amplification of pain or hyperalgesia, as well as a lengthened persistence of the pain.[3]
• Referred pain: When there is pain perception at a location other than the site of the painful stimulus, it is known as referred pain. The classical example of referred pain involves pain brought down the neck, shoulders, and back following a myocardial infarction. There is no current consensus regarding the true mechanisms behind referred pain, and there are several theories.  Referred pain may be visceral or somatic, with the former describing pain from an organ and the latter describing pain from the deep tissues such as muscles or joints. In the Ruch’s 1961 convergent-projection theory, where afferent visceral sensory pain fibers and somatic fibers enter the same spinal dorsal root ganglia segments of the spinal cord, causing the CNS to misinterpret the pain as arising from somewhere on the body wall rather than from the viscera. Somatic referred pain occurs when spinal structures such as discs or joints receive a noxious stimulus, and the pain is subsequently interpreted to be localized in the deep tissues - most commonly those of the lower extremity. This is proposed to occur by neurons that innervate these somatic tissues converging with nociceptive afferent neurons on the same second-order neurons in the spinal cord.[18][19][20][21][22]