Introduction

Pain is defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” It is a complex multidimensional concept that includes a sensory component, assessment of that sensory component, and perception and cognitive appraisal to determine whether or not the sensation is associated with suffering, and pain behaviors initiated in response to the unpleasant sensation. Pain serves a protective function in alerting a person to tissue damage or threats to bodily integrity and survival. However, the pathways that convey pain from body surface and organs to brain are subject to modulation at multiple levels, which can alter sensitivity and reactivity of the pain pathways over time. Genetics, internal metabolic factors, emotional states, and ambient variables, such as temperature and barometric pressure, all impact these built-in modulatory mechanisms. As a result of this wired-in capacity for modulation, also called plasticity , of the peripheral and central pain pathways, these mechanisms are acted upon by factors internal and external to individuals. Plasticity can dampen or intensify pain across time. Therefore, pain intensity experienced by a particular individual suffering from disease or injury, can vary greatly over time. Plasticity also leads to significant differences in pain intensity experienced across individuals suffering similar illness or injury and between experimental subjects exposed to the same standardized pressure, chemical, heat, or cold stimuli. In certain unfortunate patients, somatosensory signaling can be modulated at the spinal and supraspinal levels to create chronic pain states with much more intense pain levels and suffering than usually seen in association with similar injuries or diseases.

Nociception Versus Pain

Somatosensation is the physiologic result of transduction of a physical stimulus into a neural signal that activates afferent pathways resulting in the sensations of touch (mechanoreception), temperature (thermosensation), and pain (nociception). Noxious stimuli activate neural pathways that convey signals that ultimately lead to pain perception. Nociception refers to the neural processes associated with pain, as distinguished from the unpleasant sensory and emotional experience that is pain. Nociceptors are primary afferent neurons activated by noxious stimuli. Nociceptors have free nerve endings in the periphery, cell bodies located in the dorsal root ganglia, and axons that make first-order synapses with spinal cord cells. Conversion of noxious peripheral stimuli (physical or chemical) into electrical energy (action potential) is called transduction . Transduction occurs in the free nerve endings of nociceptors and makes possible communication of peripheral noxious stimulation to the central nervous system. Transmission is the receipt (from nociceptors) and communication through spinal cord cells to higher brain centers. Communication to supraspinal centers starts when the primary (first-order) afferents or nociceptors synapse with second-order central transmission cells in the dorsal horn of the spinal cord. These second-order cells are part of ascending pathways that convey stimuli transduced by nociceptors to the brainstem, thalamus, limbic structures, and finally to neocortex. Psychological, metabolic, and ambient factors can trigger modulation of aspects of nociception from spinal through cortical levels. The end result of pain transmission is conscious experience of pain as a multidimensional experience involving emotional, sensory-discriminative, and behavioral components.

In the sections that follow, we describe each of the aforementioned aspects of ascending pain signaling from periphery to brain pain processing, including afferent mechanisms such as transduction, central transmission through spinal pathways, and brain areas activated by these pathways. The discussion of ascending pathways is followed by a description of the top-down or descending modulation of pain signals from brain to periphery.

Peripheral Mechanisms

Nociception, somatosensation involving noxious stimuli, begins with transduction at free nerve endings and activation of primary peripheral afferent fibers. Cell bodies of these peripheral afferents as mentioned are located in the dorsal root ganglia. These fibers can be grouped into three classes with distinct behaviors and conduction velocities (see Box 1.1 ). Nociceptors include the smallest fibers Aδ- and C-fibers. Their stimulation can cause a dual pain sensation as that seen with an intense brief heat stimulus. Aδ-fibers, which conduct faster than C fibers, transmit the first pain sensation, which is felt as a prickling pain of rapid onset. The second pain sensation, transmitted by slower C-fibers, is a delayed aching or burning sensation. In addition to being classified based on conduction velocity, nociceptors can be further subclassified based on molecules expressed on their cell surface, molecules they store and release, and enzymes they contain. Noxious stimuli must be converted to chemical and electrical signals, however, before they can be propagated along Aδ- and C-fibers.

For noxious stimuli to travel from the periphery to the brain, it first has to be encoded into signals appropriate for the architecture of the nervous system. Transduction is this process of encoding touch, temperature, pressure, and other stimuli in the periphery into electrochemical signals. The free nerve endings of primary afferent fibers directly carry out this transduction function, with multiple factors functioning to modulate pain transduction.

One of the most important modulators of pain transduction is the microenvironment and chemical milieu in which it occurs. In the setting of tissue injury, inflammation contributes many potent modulators. Factors such as bradykinin, serotonin, and histamine all have dual roles in initiating the inflammatory response to tissue injury as well as mediating pain. Other cell-derived factors such as eicosanoids (arachidonic acid derivatives, including prostaglandins, thromboxanes, and leukotrienes) also act directly on nociceptors in potentiating pain. Further inflammatory contributors to peripheral modulation include cytokines such as tumor necrosis factor α that act to sensitize nociceptors. Compensatory mechanisms balance these factors and dampen pain transduction and nociceptor sensitization. Afferent fibers upregulate opioid receptors in the setting of inflammation. γ-Amino-butyric acid (GABA) may affect transduction differently depending on local factors, increasing or decreasing transduction. Somatostatin also helps counteract excessive cytokine activity. Acetylcholine acting at muscarinic receptors can desensitize C-fibers. After stimulus transduction, primary nociceptive afferents from the body surface synapse with spinal cord transmission cells in the dorsal horn while those from the face make their first synapse in the spinal trigeminal nucleus.