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Central System

The primary afferent summarizes nociceptive information from the periphery and feeds this information centrally into the spinal cord. But first, it passes through the cell body of the axon—the DRG. The DRG is the bulbous portion of the nerve seen in the neuroforamen of the spine. It is a pseudo-unipolar type neuron, meaning there is an axon on either side of the cell body that together act as a single axon. Small glial cells surround and support these cells. Nutrients are supplied via gap junctions. The DRG is the control center for the neuron, housing the genetic code for the nerve, and, as such, synthesizes neuropeptides. It follows that the DRG is a powerful modulatory location—more on this in future chapters.

Spinal Cord

The primary afferent continues through the dorsal root to the dorsal column where the first synapse occurs. Here innocuous and noxious information diverges. First, a final brief note on innocuous information. The large myelinated primary afferent non-nociceptive fibers traverse the top of the dorsal horn through Lissauer’s tract and then ascend the spinal cord through the white matter of the dorsal column or decussate to the contralateral ventral spinothalamic tract.2

Nociceptive information enters Lissauer’s tract and then innervates the gray matter of the dorsal horn where primary afferents finally synapse in the dorsal horn of the spinal cord. In the dorsal horn of the spinal cord, neurotransmission occurs via two mechanisms. Glutamate released from the primary afferent and mediated by the a-amino-3-hydroxy-5-methyl-4-isoxaz olepropionate (AMPA)-type glutamate receptor produces a robust but short-lasting depolarization of the second-order neuron.2 The second mechanism consists of peptides that produce a delayed and longer-lasting discharge as compared to the AMPA receptors. These peptidergic neurons contain peptide neurotransmitters such as CGRP, substance P, and growth factors such as brain-derived neurotropic factor. Peptides can enhance nociception, thus playing a role in central sensitization.2

Dorsal Horn Excitability

It is the dorsal horn synapse which allows for significant modulation of the pain signal. Inhibitory modulation pathways are both supraspinal as well as local. We will look at local modulation first. While all neurons synapse at least once before continuing their ascent to the brain, some neurons experience multiple synapses where interneurons can affect transmission. Most of the nociceptive neurons synapse in the superficial portion of the dorsal horn within the anatomic locations of Rexed laminae I and II. Laminae II contains interneurons that modulate the signal with either excitatory or inhibitory neurotransmitters. Glutamate is the excitatory neurotransmitter while y-aminobutyricacid (GABA) is the inhibitory neurotransmitter. GABA and glycine are major inhibitory neurotransmitters which are active both pre-synaptic as well as post-synaptic. GABA serves as a ligand for both GABAa and GABAB receptors. Both GABAa and glycine receptors increase CL conductance.

GABAB functions as a G protein-coupled receptor. GABA and glycine have more of an impact on the larger A(3 fibers than the smaller fiber types. The modulation is not that simple and other modulatory substances are also found in the dorsal horn including adenosine, choline acetyltransferase, CCK, corticotropin-releasing factor, dynorphin, enkephalin, galanin, glycine, neurotensin, neuropeptide Y, somatostatin, substance P, and thyrotropin-releasing hormone. Each of these substances modulates the signal in various ways.

Lamina V contains wide dynamic range (WDR) neurons responding to both painful and non- painful stimuli. A(3 fibers typically project into lamina III and deeper. High-threshold C fibers project into the more superficial lamina I and II. Following peripheral nerve injury, it has been noted that A fibers can sprout into the more superficial lamina I and II, resulting in low-threshold mechanoreceptor activation being interpreted as deep pain.2

Supraspinal Modulation

In addition to local signal modulation, there are supraspinal pathways that impact the dorsal horn. The supraspinal pathway (or descending pathway) originates from the brain and travels to the dorsal horn of the spinal cord, creating a top-down component utilizing serotonin and norepinephrine. Midbrain periaqueductal gray (PAG), dorsolateral pons, and rostroventral medulla all play important roles in this descending pain pathway. The descending pathways were originally considered as a pain inhibition pathway only. However, it is now known that these descending pathways can be both facilitatory as well as inhibitory.

The midbrain’s PAG plays a central role in the descending pain pathway. The hypothalamus has topographic projections onto the PAG. Forebrain projections from the limbic system are also noted. Together, these regions affect the PAG to project to the rostroventral medulla (RVM) and the pons, utilizing substance P, glutamate, and cholinergic neurons to impact the pain processing system. Opiate receptors are noted in the PAG (as well as the amygdala and midline medulla). Opiates inhibit the inhibitory (GABA) output to the medulla. As a result, the bulbospinal pathway is activated via noradrenergic and serotoninergic pathways.

In the pons, the locus coeruleus projects norepinephrine toward the spinal cord as well as into the thalamus and forebrain. The forebrain projections appear to alter affective components of behavior, while the spinal projections inhibit pain transmission in the dorsal horn via a, receptors on the dorsal horn. a2 receptor binding is both pre-synaptic on the C fibers and post-synaptic on the dorsal horn neurons. Opiates inhibit the activity of the cells of the locus coeruleus. During withdrawal from opiates, the increased activity of these cells becomes symptomatic. Clonidine has been used as an antagonist to blunt the withdrawal effect.

The nucleus raphe magnus in the caudal pons/rostral medulla projects serotoninergic neurons spinally toward the dorsal horn of the spinal cord as well as the limbic forebrain. Here, serotonin may actually excite pain processing. This pathway may play an important role in pain chronifica- tion. This pathway may also hold insight as to how higher centers can impact the nocebo effect.9 This may occur via neurotopins. Specifically, BDNF from the PAG binds to TrkB in the RVM. This process is mediated by NMDA receptors.9 In addition, neuron-glial interactions play a role when nerve injury is present by the CCL2 chemokine binding to astrocytes in the RVM.10 The prefrontal, anterior cingulate cortex (ACC) and amygdala coordinate this inhibitory and excitatory balance.1'-13 It appears as though the analgesic properties of antidepressants may be mediated more by their impact on norepinephrine than on serotonin.

Projections from the rostral ventromedial medulla (RVM) directly synapse with the dorsal horn of the spinal cord. These cells are both serotonergic and non-serotonergic. In addition, there are cells from the RVM that project back to the dorsolateral pons, utilizing enkephalin as inhibitory and SP as excitatory neurotransmitters.

Diffuse noxious inhibitory controls (DNICs) are a spinal-medullary-spinal mechanism where harmless but noxious stimuli may inhibit the responsiveness of WDR neurons in the spinal cord.9

This pathway is not dependent on the PAG or RVM. Rather, it is dependent on a supraspinal loop through the dorsal reticular nucleus.2

In addition to sustained C fiber input activating wide dynamic range neurons, there is direct communication witli the medullary raphe nuclei that results in the excitation of bulbo-serotonin pathways that activate 5-hydroxytyptamine (5-HT3) receptors on lamina V neurons. The use of 5-HT, inhibitors can reduce this state.14

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