Pain Anatomy and Physiology

Damoon Rejaei, MD

Samir J. Sheth, MD

FAST FACTS

Pain transmission and sensation is a complex phenomenon composed of multiple components including nociceptor activation, ascending spinal tracts, descending spinal tracts, and higher brain centers.
Various nociceptors and chemical mediators are involved in experiencing different pain sensations from thermal, mechanical, or chemical stimuli.
Chronic pain can result from peripheral sensitization, central sensitization, or both.

INTRODUCTION

Although pain is experienced by nearly the entire human species, defining and detecting pain in humans can be elusive. For millennia, describing and defining pain has been of great interest. Indeed, Aristotle (384-322 BC) argued that pain was an emotion and associated it with the heart. In contrast, Galen (AD 130-201) emphasized the brain as the organ of feeling and placed pain into the realm of the mind.¹ In 1906, Sir Charles Sherrington explicitly distinguished between the complex human experience of pain and that of nociception by defining nociception as the sensory detection of a noxious event or a potentially harmful environmental stimulus.² The ability to detect noxious stimuli is fundamental to the survival of an organism, as witnessed by the early death of people who carry rare recessive genotypes rendering them congenitally insensitive to pain. In modern times, a more comprehensive view is upheld on the definition of pain. The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage.”³

The pain system grossly spans the entire neuraxis. This is evidenced by the fact that both the peripheral destruction of tissue and the psychological distress of trauma can often lead to similar patient reports of pain. The fundamental mechanisms behind these similar experiences, however, must be different. Moreover, despite the termination of an acutely painful stimulus, the patient with chronic pain continues to live with an “unpleasant sensory and emotional experience.” This chapter attempts to elucidate the fundamental anatomy and physiology responsible for chronic pain. Grossly, the pain system can be divided into the following components:

Nociceptors: Peripheral nerve fibers that detect noxious stimuli (i.e., thermal, mechanical, or chemical).

The spinal cord and ascending nociceptive tracks: Projection neurons that carry pain signals from the dorsal horn of the spinal cord to higher centers of the central nervous system (CNS), such as the brain.

Higher centers in the CNS and descending inhibitory tracts: These pathways allow for the modulation of pain from higher CNS structures to the spinal cord.

NOCICEPTORS

Nociceptors are a population of peripheral neurons responsible for detecting painful stimuli. Their cell bodies are located in the dorsal root ganglion (DRG) for the body and in the trigeminal ganglion for the face. As such, in the body, nociceptors have their cell bodies located in the peripheral nervous system (PNS), whereas in the face their cell bodies are located in the CNS. Interestingly, nociceptors are pseudounipolar, meaning their axonal projections divide to travel both centrally to the
spinal cord (and from there to higher brain centers) and peripherally to the skin and other organs (Figure 2-1). Classically one imagines information in neurons to travel in one direction with a clear linearity between dendritic input of information to the cell body and the axonal output of neurotransmitters. However, the pseudounipolar nature of nociceptors allows for the bidirectional travel of information. This is significant because therapeutic drugs can target the peripheral axonal terminal (i.e., anti-inflammatory medication) to prevent nociceptor activation and/or the central axonal terminal (i.e., intrathecal drug delivery) of nociceptors to prevent neurotransmitter release at the level of the spinal cord.⁴^,⁵

FIGURE 2-1 Pain pathways. Primary (1°) nociceptors have cell bodies in the dorsal root ganglion and synapse with secondary (2°) afferent neurons in the dorsal horn of the spinal cord. Primary afferents use the neurotransmitter glutamate. The 2° afferents travel in the lateral areas of the spinal cord and eventually reach the thalamus, where they synapse with tertiary (3°) afferent neurons. The processing of pain is complex, and 3° afferents have many destinations, including the somatosensory cortex (localization of pain) and the limbic system (emotional aspects of pain). Reprinted with permission from Golan DE. Principles of Pharmacology. 4th ed. Philadelphia, PA: Wolters Kluwer; 2016.

There are 2 major classes of nociceptors: medium-diameter thinly myelinated Aδ neurons and small-diameter unmyelinated C fiber neurons.⁶ Both Aδ and C fiber afferents are further subdivided into other classes, which is beyond the scope of this chapter. These afferent nerves can detect thermal, mechanical, or chemical environmental stimuli. Aδ and C fibers are only a subset of sensory fibers present in the PNS (Table 2-1). Given their thin and myelinated axons, Aδ fibers mediate acute and precisely localized pain. In contrast, C fibers mediate poorly localized and delayed pain.

Nociceptor Activation

Nociceptors are activated by a variety of environmental stimuli, including thermal, mechanical, and various chemical stimuli. The pain threshold for heat activation of nociceptors in both Aδ and C fibers has been found to typically rest around 43°C.⁷ The transient receptor potential (TRP) group of ion channels are activated by heat. One of the most studied members of this family of ion channels is the TRPV1 receptor, which was identified as the molecular target for capsaicin, the pungent component of “spicy” or “hot” chili peppers. Indeed, mice that genetically lack this TRPV1 receptor show significant impairment in their ability to detect noxious heat stimuli.⁸ Under normal physiological conditions, heat or acidosis can lead to the transient opening of TRPV1 channels, which in turn leads to calcium and sodium influx into the cell and action potential propagation into the spinal cord. Interestingly, in contrast to transient activation of the TRPV1 channel, high concentrations or repetitive exposure to capsaicin can cause persistent opening of the TRPV1 channel. This in turn, leads to a large influx of calcium into the cell, leading to activation of calcium-dependent proteases and cytoskeleton breakdown (i.e., receptor inactivation). This is how topical capsaicin formulations are used to treat a variety of pain conditions (i.e., postherpetic neuralgia).⁹

A variety of chemical mediators and environmental toxins can trigger nociceptor activity. TRPA1, another member of the TRP group of ion channels, has been found to respond to a variety of environmental compounds such as allyl isothiocyanate (from the wasabi plant) or allicin (from garlic). Acrolein, an environmental toxin found in vehicle exhaust and tear gas, can also activate the TRPA1 channel, leading to pain in the eyes and airways. This can have a more severe impact in patients suffering from respiratory diseases (i.e., asthma).¹⁰ To highlight the role of TRPA1 channels, mice lacking the TRPA1 gene show significantly reduced reactivity to the aforementioned chemicals.¹¹

As a result of tissue damage and inflammation, certain endogenous chemical mediators can also contribute to the pain process. These chemicals are often termed to be the “chemical milieu of inflammation.” In the event of tissue damage, a variety of cells such as mast cells, basophils, platelets, macrophages, and neutrophils infiltrate
the injured area. These cells release a variety of chemicals such as neurotransmitters, peptides (substance P, CGRP, bradykinin), lipids (prostaglandins, leukotrienes, endocannabinoids), and cytokines. These chemicals can then bond to certain receptors (such as TRPV1, TRPA1) on the nociceptors and hence lead to their activation. A variety of drugs such as nonsteroidal anti-inflammatory drugs (i.e., ibuprofen and aspirin) reduce this inflammatory pain by inhibiting prostaglandin synthesis through cyclooxygenase 1 and 2 inhibition.

TABLE 2-1 Fibers of the Peripheral Nervous System

FIBER TYPE	PHYSIOLOGIC ROLE	PAIN QUALITY	FUNCTION	MYELINATED	AVERAGE DIAMETER (µm)	AVERAGE CONDUCTION VELOCITY (m/s)
A α	Motor		Muscle spindle, motor to skeletal muscle	Yes	15	100
A β	Sensory		Proprioceptive, touch, pressure	Yes	8	50
A γ	Motor		Skeletal muscle tone	Yes	6	20
A δ	Sensory	Rapid, sharp, localized	Nociceptive, touch, temperature	Yes	2	15
B	Sympathetic		Preganglionic, controls vascular smooth muscle	Yes	3	9
C	Sensory	Slow, diffuse, dull	Nociceptive, touch, temperature, also postganglionic, controls viscera and afferent relay to skin	No	1	1
Adapted from Cousins MJ, Bridenbaugh PO. Neural Blockade in Clinical Anesthesia and Management of Pain. 3rd ed. Lippincott Williams and Wilkins; 1998:44-45 and Wainger B, Brenner GJ. Mechanisms of chronic pain. In: Longnecker DE, Mackey SC, Newman MF, Sandberg WS, Zapol WM, eds. Anesthesiology. McGraw-Hill Education; 2018:1441-1455