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and facilitory input from the brain that influences (modulates) nociceptive transmission at the level of the spinal cord. 4 Pain: Current Understanding of Assessment, Management, and Treatments Section I: Background and Significance 3. What Happens During Transduction? a. Nociceptor activation and sensitization Nociceptors are sensory receptors that are preferentially sensitive to tissue trauma or a stimulus that would damage tissue if prolonged.19 These receptors are the free endings of (primary afferent) nerve fibers distributed throughout the periphery (Figure 1). Signals from these nociceptors travel primarily along two fiber types: slowly conducting unmyelinated C-fibers and small, myelinated, and more rapidly conducting Adelta fibersc (Figure 2). Injury to tissue causes cells to break down and release various tissue byproducts and mediators of inflammation (e.g., prostaglandins, substance P, bradykinin, histamine, serotonin, cytokines).24,25 Some of these substances activate nociceptors (i.e., cause them to generate nerve impulses) and most sensitize nociceptors (i.e., increase their excitability and discharge frequency).26,27 Ongoing activation of nociceptors may cause nociceptive pain (see I.B.9). Peripheral (nociceptor) sensitization amplifies signal transmission and thereby contributes to central sensitization and clinical pain states (see I.B.7-8).28 b. Peripheral neuropathic pain Not all pain that originates in the periphery is nociceptive pain. Some neuropathic pain is caused by injury or dysfunction of the peripheral nervous system (i.e., peripheral nerves, ganglia, and nerve plexi)(see I.B.10)(Figure 1).22 c. Clinical implications Some analgesics target the inflammatory process that produces sensitization. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX), thus decreasing the synthesis of prostaglandins.29-30 Other analgesics (e.g., antiepileptic drugs, local anesthetics) block or modulate channels, thus inhibiting the generation of nerve impulses. National Pharmaceutical Council 5 Section I: Background and Significance Figure 1. cIn addition to these nociceptors, A-beta fibers (which normally subserve touch) sometimes act as nociceptors when sensitized. The functioning of nociceptors depends upon the electrophysiological properties of the tissues, co-factors, and cytokines.24 Source: Reference 22. Peripheral origins of pain. Noxious signaling may result from either abnormal firing patterns due to damage or disease in the peripheral nerves or stimulation of nociceptors (free nerve endings due to tissue trauma). Inflammation in injured or diseased tissue sensitizes nociceptors, lowering their firing thresholds. Some clinical pain states have no peripheral origin, arising from disorders of brain function. 4. What Is Transmission? Nerve impulses generated in the periphery are transmitted to the spinal cord and brain in several phases:21,31 a. Periphery to the spinal cord Most sensory nerve impulses travel via the nerve processes (axons) of primary afferent neurons to the dorsal horn (DH) of the spinal cord (Figure 2).32 There, primary afferent neurons propagate nerve impulses to DH neurons through the release of excitatory amino acids (EAAs) (e.g., glutamate, aspartate) and neuropeptides (e.g., substance P) at synapses (connections) between cells.d,39 Activated DH projection neurons forward nociceptive impulses toward the brain. However, not all events in the DH facilitate nociception. Spinal interneurons release inhibitory amino acids (e.g., γ-aminobutyric acid [GABA]) and neuropeptides (endogenous opioids) that bind to receptors on primary afferent and DH neurons and inhibit nociceptive transmission by presynaptic and postsynaptic mechanisms.39-42 Descending inhibitory input from the brain also modulates DH nociceptive transmission (see I.B.6) (Figure 3). Thus, nociceptive traffic in the DH is not merely relayed to higher centers but rather is heavily modulated. These inhibitory events are part of a natural nociceptive-modulating system that counterbalances the activity of the nociceptive-signaling system. b. Spinal cord to the brain The nerve processes of DH projection neurons project to the brain in bundles called ascending tracts. Projection neurons from some DH regions transmit nociceptive signals to the thalamus via the spinothalamic tract (STT) (Figures 2, 4).39,43 Others transmit nociceptive information to the reticular formation, mesencephalon, and hypothalamus via the spinoreticular, spinomesencephalic, and spinohypothalamic tracts (Figure 4).22,44 c. Clinical implications Some analgesics inhibit nociception in the 6 Pain: Current Understanding of Assessment, Management, and Treatments Section I: Background and Significance Figure 3. Source: Reference 22. A simplified view of spinal cord mechanisms. Afferents conveying noxious signaling from the periphery enter the dorsal horn of the spinal cord, where they synapse with dorsal horn neurons. This generates nerve impulses that exit the cord ipsilaterally through motor and sympathetic efferents. Other activity produces signals that ascend to various areas in the brain. This simple sketch shows only the anterolateral funiculus, which ascends to the brain stem and thalamus. Inhibitory influences include certain spinal interneurons and descending pathways from periadqueductal gray and other areas (dashed line). Figure 2. Source:
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