Chapter 1. Molecular Biology of Pain

“Stimuli become adequate as excitants of pain when they are of such intensity as threatens damage to the skin.”

Sherrington (1906)1

The acute activation of small sensory afferent axons by high-intensity thermal and mechanical stimuli evokes locally organized spinal motor reflexes (nociceptive reflexes), autonomic responses, and pain behavior in animals and humans. This effect is mediated by the local encoding of afferent input at the level of the dorsal horn and the activation of spinofugal projection neurons. These projection systems travel both ipsilaterally and contralaterally in the ventrolateral aspect of the spinal cord, projecting supraspinally into the medulla, mesencephalon, and diencephalon. Medullary projections serve to activate spinobulbospinal reflexes that influence autonomic tone. Other projections into the mesencephalon and thalamus are assumed to contribute to the perceptual and complex emotive and discriminative components of the pain state. It is important to appreciate that the encoding by the sensory afferent and the spinal dorsal horn of the nociceptive stimulus is the first step in nociceptive processing, and this encoding process contributes properties that are important to the understanding of the behavioral correlates of nociception. The following sections consider aspects of the mechanisms whereby injury leads to an ongoing pain state from the perspective of the organization of the sensory afferents and the spinal dorsal horn. Of particular importance is the appreciation that these linkages have distinct pharmacologies and that these systems can be regulated to display prominent increases (hyperalgesia) and decreases (analgesia) in the input-output function.

Morphology

Sensory afferents represent the first link between the nervous system and the peripheral milieu. Whether they are enteroceptive organs such as viscera or blood vessels, the meninges, deep structures such as muscle or joint, or the skin, all surfaces are innervated by axons that transduce the local milieu to generate action potentials that provide input to the neuraxis. These primary afferent axons are constituted of the central (root) and peripheral (nerve) projections and the dorsal root ganglion cell body that is connected to the root by a sinuous glomerulus. With the exception of several cranial nerves, all axons have their primary cell body in the dorsal root ganglia that lie outside of the neuraxis proper.2

Normal Sensory Afferent Activity

Classification of Sensory Afferents

These axons may be classified according to the nature of the peripheral terminals, their size (large or small), state of myelination (myelinated or unmyelinated), and, functionally, according to their conduction velocity (large axons are rapid; small axons are slower) and to the modality of stimulation that most effectively results in activity in the associated axon.

Sensory Nerve Endings

It is important to emphasize that the peripheral afferent terminal is an exceedingly specialized region. The terminal provides the transduction properties that convert stimulus of a given modality into a local ...