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2 Nociceptive processing: How does pain occur?

Nociceptive processing is the processing of pain‐related information by the nervous system, occurring at many levels. By understanding how pain is processed in the body, we can better understand patients' pain.

Both neurons and glia participate in nociceptive processing and responses to nociceptive inputs are shaped by genetic and environmental factors, explaining the tremendous variation in pain experience.

The nociceptive processing system is anatomically and functionally divided into four inter‐related components: transduction, transmission, perception, and modulation (Figure 2.1). Normally, nociceptive processing serves to protect an organism. Unfortunately, fidelity in recognizing threats is sometimes lost, and misdirected activation results in aberrant pain sensing (enhancement or loss). In this respect, the pain system is not unlike the immune system which can manifest disorders of excessive or deficient immunity, both causing substantial harm. Excessive pain, persistent pain, and deficient pain perception are all detrimental to health.

Figure 2.1 Simplified overview of nociceptive processing in the nervous system.

Transduction

Pain perception normally begins with a noxious stimulus. Perhaps a thorn is encountered: nerve endings of thinly myelinated and unmyelinated axons respond. Many decades ago, there was vigorous discussion about the “labeled line” hypothesis. The idea was that “pain” was encoded by specific nerve fibers and travelled in a dedicated pain system. With molecular biology, we know now that there are a wide variety of “labeled lines” each carrying signals of a particular flavor or nuance (Stucky et al. 2009; Ringkamp et al. 2013). For example, various transient receptor‐potential (TRP) channels are expressed in sensory neurons responding to high heat, medium heat, low heat, warm, and cold stimuli across the thermal spectrum, similar to the way that rods in the eye respond to different spectral intensities of light (Tominaga et al. 1998; Fernández‐Carvajal et al. 2012). Some of these thermal stimuli are clearly encoded as painful, some require co‐activation of other sensory afferents to produce a painful percept. Transduction occurs in response to different forms of stimulus, e.g. mechanical, thermal, chemical. Signaling ions enter the primary afferent peripheral nerve termination causing small shifts in membrane potential: the “graded potential.” If the graded potential shifts the local membrane potential to threshold, action potentials volley into the afferent axon. Altered transduction by nerve endings in the target organ is an important part of inflammatory pain; mediators such as NGF, bradykinin, and protons can sensitize nerve endings, leading non‐ painful stimuli to produce pain.

Transmission

Nociceptive signals are transmitted as action potentials via multiple structures in parallel and series. The primary afferent neuron, with cell body located in the dorsal root ganglion, extends axons peripherally and centrally from the sensory ganglion. Many nociceptive signals are transmitted by small nerve fibers of varying caliber. “First pain,” for example, is signaled by thinly myelinated a‐delta fibers that conduct action potentials at about 20 m/s. This means that an adult leg can be traversed in under 50 ms. So‐called “second pain” is signaled by unmyelinated C fibers that conduct at 1 m/s and arrive at the spinal cord much later. Both fast and slow signals are transmitted to second order neurons in the spinal dorsal horn. The synapses are principally located about two anatomical levels rostral to the entry of the root into the spinal cord. Lumbar and sacral spinal roots terminate far rostral to the corresponding vertebra, with implications for spinal lesion localization. Cervical roots are much shorter. Altogether, nerves, spinal cord, brain stem, and cortical white matter are all involved in transmission.

Perception

The perception of pain is multidimensional and occurs in several cortical sites. S1 and S2 are associated with the sensory‐discriminative features of pain. The earliest activation of cortex in response to pain is in the “S2” sensory‐discriminative area (Granovsky et al. 2008). The medial limbic cortex, (rostral anterior cingulate cortex) mediates the affective, motivational aspects of pain. Other structures contribute to the impact of pain on motor behavior (basal ganglia and cerebellum), sympathetic tone (insula), and alertness (periaqueductal gray) (Liu et al. 2011). It is arguable whether all are properly referred to as “perception” but a better term has not arisen. Perception occurs as a complex temporal and spatial series of events varying with the type, severity, and persistence of pain. Neuropathic pain results in strong activation of affective and motivational centers in the brain. Unfortunately, persistent pain may be associated with brain atrophy (Baliki et al. 2011).

Modulation

Pain modulation occurs at every level of the nervous system including end‐organs, peripheral nerve, spinal dorsal horn and rostral centers. Key modulation events occur in the dorsal spinal cord where descending fibers, especially from the nucleus raphe magnocellularis (NRM) synapse and control the transmission of nociceptive signals from primary afferent neurons onto second order neurons (Figure 2.2). This is an important form of gating which has the potential to constrain “pain from accessing the CNS.” The NRM is situated in the ventral midline at the pontomedullary junction. It contains both “ON” and “OFF” cells. ON cells have the capacity to sensitize an animal to noxious stimuli, effectively turning the pain system “on,” whereas OFF cells have the capacity to decrease the transmission of nociceptive signals from primary to secondary afferent, effectively turning pain sensitivity “off.” More recently, a role for non‐neuronal cells has been recognized in nociceptive modulation (see Chapter 29).

Figure 2.2 Transmission and modulation events in the spinal dorsal horn. Influences on nociceptive processing include: descending inhibition and facilitation, afferent inputs from the periphery and local inhibitory circuits. This is a key site of drug action.

In summary, pain experience arises from the normative functioning of the nociceptive processing system, a complex sub‐system of the nervous system including both neuronal and non‐neuronal elements. Understanding the component elements of the pain processing system: transduction, transmission, perception, and modulation, may aid clinicians in thinking about patients with pain, and lead them to develop more effective diagnostic and treatment plans.

References

1 Baliki, M.N., Schnitzer, T.J., Bauer, W.R., and Apkarian, A.V. (2011). Brain morphological signatures for chronic pain. PLoS One 6 (10): e26010.

2 Fernández‐Carvajal, A., Fernández‐Ballester, G., Devesa, I. et al. (2012). New strategies to develop novel pain therapies: addressing thermoreceptors from different points of view. Pharmaceuticals 5 (1): 16–48. https://doi.org/10.3390/ph5010016.

3 Granovsky, Y., Granot, M., Nir, R.‐R., and Yarnitsky, D. 'Correspondence information about the author David Yarnitsky (2008). Objective correlate of subjective pain perception by contact heat‐evoked potentials. Journal of Pain 9 (1): 53–63.

4 Liu, C.C., Franaszczuk, P., Crone, N.E. et al. (2011). Studies of properties of “Pain Networks” as predictors of targets of stimulation for treatment of pain. Frontiers in Integrative Neuroscience 5: 80.

5 Ringkamp, M., Raja, S., Campbell, J., and Meyer, R. (2013). Peripheral mechanisms of cutaneous nociception. In: Wall and Melzack’s Textbook of Pain, 6e (eds. M.M. SB, M. Koltzenburg, I. Tracey and D. Turk). Philadelphia, PA: Elsevier Saunders.

6 Stucky, C.L., Dubin, A.E., Jeske, N.A. et al. (2009). Roles of transient receptor potential channels in pain. Brain Research Reviews 60 (1): 2–23.

7 Tominaga, M., Caterina, M.J., Malmberg, A.B. et al. (1998). The cloned capsaicin receptor integrates multiple pain‐producing stimuli. Neuron 21 (3): 531–543.