Pain+Modulation

Introduction
Pain is an adaptive sensation that allows humans to detect when the body has sustained damage. However, it is highly uncomfortable, and persists long after we have taken measures to address it. Modern medicine has developed many different forms of pain killers, but the body itself is designed to modulate pain which helps reduce discomfort once the person is aware of the initial signal.

If you are simply interested in pain modulation specifically, jump to that section below, otherwise, a brief review of some anatomy and physiology will follow to preface the material.

Ins, Outs and Structures: A Review of Pain
__Input __

Pain is a vital piece of sensory information. There are specialized receptors for it, called nociceptors, which allow the body to recognize temperature, chemical and mechanical stimuli that are potentially tissue damaging. These receptors are located throughout the body, such as cutaneous nociceptors. The axons of the pain carrying afferents are the A-delta and C fiber varieties. This means that they conduct action potentials more slowly than most axons in the body. A-delta fibers carry their signals more quickly though, as C fibers are not even myelinated (this is the basis of double pain: A-delta fibers carry the initial stimulus more quickly up to the brain, first pain, then the C fiber information arrives, and since they are slow adapting, this second pain is longer lasting, but duller). The neurons have their cell bodies in the dorsal root ganglion, and their axons enter through the dorsal root, where they make their first bifurcation. One side of the axon goes into the spinal cord and synapses in Rexed’s Lamina I (A-delta) or II (C) (Squire et al., 2003), and some in Lamina V (Blumenfeld, 2002). See Figure 1. The other side of the axon travels a few segments up or down in a region called the Zone of Lissauer or substantia gelatinosa before entering the dorsal horn and synapsing (Bear et al., 2007). See Figure 2. This Lissauer’s tract may be the reason pain can be difficult to localize at times, but might have evolved so as to maintain the ability to perceive pain should damage be sustained to the spinal cord. The cell bodies of the second order afferents are in the ipsilateral dorsal horn. Their axons then decussate through the anterior white commissure and ascend in anterolateral tract, along with axons carrying information about crude touch and temperature. See Figure 3.

 

The anterolateral tract is a region of the spinal cord where a specific type of information ascends. There is some somatotopic arrangement, with upper body being more posterior and lateral, and lower body being more anterior and medial (Blumenfeld, 2002). However, this is simply a region of the spinal cord, while pain afferents have more specific locations for termination. See Figure 4 for an image of the following explanation.



The most direct pathway for pain, and that which allows an individual to become conscious of it, is the spinothalamic pathway (spinothalamic is labeled as paleospinothalamic in Figure 4). The bulk of the axons in the anterolateral tract follow this pathway, and there is the most organization in its terminations than the other two. This pathway stays in the anterolateral region of the spinal cord all the way up until it syna pses with the third order neurons in the ventral posterolateral nucleus of the thalamus. The thalamus then sends somatotopically arranged afferents to the primary somatosensory cortex, where the location of pain can be discriminated. Some collateral axons also synapse in the medial nucleus of the posterior complex and the central lateral nucleus in the thalamus (Squire et al., 2003). Two other termination sites for the anterolateral system are important, especially for pain modulation.

The spinoreticular tract refers to the collateral branches of axons in the anterolateral tract which synapse in both the pontine and medullary reticular formation. The post synaptic cells then connect with the intralaminar thalamic nuclei (centromedian nucleus) which brings the information up to the cortex (Blumenfeld, 2002). These connections cause arousal and affective response more than discriminating location.

Lastly, and most importantly for pain modulation, some collaterals terminate in the periaqueductal gray (PAG) of the midbrain, terminating the spinomesencephallic tract. These connections carry purely pain information, and it is these connections which are involved in one of the main pain modulation mechanisms.

__Output __

The regions important for the output of the pain modulation mechanisms are the spinal cord, the periaqueductal grey matter in the midbrain, the nucleus raphe magnus in the rostral ventral medulla (RVM) and the lateral tegmental nucleus of the medulla. The gist of pain modulation is that there are signals that modulate the activity of the synapse between the primary and second neurons in the anterolateral system, and all the latter regions contain a structure or fiber which helps inhibit the transmission of pain signals to the brain (in depth discussion to follow).

The analgesic mechanisms of the central nervous system involve a variety of neurotransmitters. Enkephalins, “analgesic oligopeptides with 200 times the potency of morphine” (Saladin, 2010) are a type of endogenous opioids, meaning they are in the same class of molecules as opium, heroine and morphine, but produced internally. Serotonin, one of the major monoamine signaling molecules in the body, also referred to as 5-hydroxytryptamine or 5-HT (Saladin, 2010). It is involved in neuromodulation. Substance P is an 11 amino acid peptide in the tachykinin class, and is involved in pain signaling among other functions (Nicholls, et al., 2001)). It’s name comes because it was first discovered in the //powdered// <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">extract of rat brain and intestine <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">(Saladin, 2010). <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Lastly, the catecholamine norepinephrine also plays a role in pain modulation (Squire et al., 2003).

Pain Modulation Mechanisms
<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">There are two main ways in which the nervous system modulates incoming pain signals. The first is what is known as gate control theory, which involves cutaneous afferents as the source of analgesic signals. The second comes in the form of descending input from subcortical structures modulating the primary and second afferent synapses in the spinal cord.

__<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Gate Control Theory __

<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 16px;">This theory accounts for the fact that rubbing or shaking an injury site helps reduce pain. The way it works is based on inhibition of the synapse between the nociceptive afferent and the secondary afferent in the spinal cord. Large diameter, non-nociceptive fibers also enter the dorsal horn and they follow their own pathway up to spinal cord. However, some also have collateral axons which synapse in an inhibitory interneuron (IN). These inhibitory IN’s synapse on the secondary afferent, and perhaps in the presynaptic sensory afferent as well (Nicholls, et al., 2001), inhibiting the interaction. When a pain signal comes in, it activates the projection neuron, sending pain signals onto the brain. However, when there is activation of the cutaneous afferents, there is activation of the IN’s, which release enkephalin. This causes profound inhibition on the post synaptic neurons (Nicholls, et al., 2001), preventing the pain signal from being transmitted. See Figure 5



<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 16px;">The presence of these enkephalin receptors is one reason why opioid drugs are effective at reducing pain. So, if a pain signal is being continuously sent through a slow adapting C fiber, and cutaneous receptors in the same area are activated through rubbing or shaking (such as shaking your hand after hitting your thumb with a hammer), then the cutaneous afferent signals inhibit the pain signals from being transmitted to the brain. The pain signals may be coming, but they are not reaching the cortex, so while there may be tissue damage, the cognitive experience and affective power of pain is inhibited.

__<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Descending Regulation __

<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">The PAG in the midbrain receives input from the hypothalamus, amygdale and the cortex. Its output neurons send enkephalinergic axons to the medulla. There they excite efferents in the raphe magnus (in the medulla) which then send serotogenic efferents to activate the inhibitory INs in the spinal cord, which then inhibit the incoming pain signals (Squire et al., 2003; Nicholls, et al., 2001). Also, the PAG has terminations in the rostral pons which result in activation of noradrenergic efferents which also excite the inhibitory INs in the spinal which then inhibit incoming pain signals (Blumenfeld, 2002). There is some debate on the exact connections of the PAG and the pons, but it seems as though the PAG excited neurons in the locus ceruleus (cluster of neurons on the pons) which then excite the noradrenergic efferents in the dorsolateral tegmental nucleus (Squire et al., 2003; Blumenfeld, 2002; Samuels and Szabadi). The end result of all these connections is inhibition of the incoming pain signals. See Figure 6 for a summary of these connections. This model also explains why opioids have analgesic effects: there are opioid receptors in the hypothalamus, nuclei in the midbrain, medulla, pons, and as mentioned before, the spinal cord.



Conclusion
<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Pain is useful, but generally avoided. The body functions to allow both, though not always to the degree which western medicine has given us the privilege of controlling. Pain signals come in and result in conscious / location based awareness as well as emotional arousal leading to exclamation and reactive behavior. However, they also allow the body to begin to modulate the signals causing the uncomfortable sensation. We have developed instinctive behaviors like rubbing a shin when we walk into a t <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">able leg or shaking a hand after touching a hot stove because experience has taught us that activation of cutaneous receptors can help dull the pain. Also, even though the brain sends signals to quiet the noxious stimulus, we have learned that we can silence them by addition ingested substances. The only reason these analgesics work is because the body has these pain modulation systems in place already. The molecules themselves hold no power without the receptor causing the correct influx of ions or silencing of a channel to prevent a cell from firing or causing it to go into overdrive. In short, the neurophysiology of pain modulation helps make sense of common experience, in the often intelligible, but nevertheless elegant and profound fashion of the human nervous system.



Glossary
<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Nociceptors – receptor which transduces painful stimuli into action potentials <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">A-delta – fiber type which is thick thickest (of four types) and is myelinated <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">C fiber – fiber type which is the smallest diameter and is unmyelinated <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Somatotopic – correspondence between the form of the body and its representation in region <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Rexed lamina – system of classifying the ten layers of gray matter in the spinal cord. Layer I is most dorsal, increasing number moving more ventral; however, Lamina X surrounds the central canal of the spinal cord <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Ipsilateral – same side <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Contralateral – opposite side <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Afferent – carrying information towards the CNS <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Efferent – carrying information away from the CNS <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Analgesic – reducing or eliminating pain <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Anterior white commissure – region of the white matter of the spinal cord directly anterior to the central canal <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Rostral – situated above, superior <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Caudal – situated beneath, inferior <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Opioid – group of substances resembling morphine in their effects; typically pain relieving <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Subcortical – structures or regions beneath the cortex, such as the brainstem nuclei

Quiz
<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">1. Which of these pathways does pain NOT travel?

<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">A spinoreticular <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">B spinocerebellar <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">C spinomesencephallic <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">D spinothalamic

<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">True of False?

<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">2. The anterolateral system does not decussate?

<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">3. The receptor for pain is called a nociceptor?

<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">4. Pain is such an important stimuli that it is one of the fastest traveling signals.

<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">5. Morphine is stronger than any analgesic the body creates.

<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">6. Pain signals go to more than just the thalamus.

<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Short answer

<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">7. In gate control theory, how does incoming cutaneous information silence incoming pains signals?

<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">8. Descending pain modulation is sometimes described as “pain inhibits pain.” Explain why this makes sense.

<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">9. Explain in brief why ingested opioids are effective.

<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">10. Why is pain modulation even necessary (why does the sensation of pain persist)?

Answers
<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">1 – B, 2 – F, 3 – T, 4 – F, 5 – F, 6 –T, <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">7 – the afferents for cutaneous input have collateral axons that excite on an inhibitory interneuron, in the spinal cord, which then inhibit the afferents carrying the pain signal <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">8 – incoming pain signals are the activation trigger for the descending pain modulation mechanisms. So pain must be induced before it can be inhibited. <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">9 – the opioid class of molecules resemble internal neurotransmitters enough that they can bind on the same receptors. In pain modulation, the neurotransmitters used include some in the opioid class, so there are receptors which can bind ingested opioids, activating pain modulation mechanisms without having to induce pain. <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">10 – incoming information from the anterolateral system lets us know when noxious stimuli impinge on our tissues. However, tissue damage is the source of nociceptors activation, and tissue damage does not instantly heal, so the pain persists because the source of the pain persists. Once we are aware of the pain, we no longer need to be continuously reminded, so internal pain modulation mechanisms help to take the edge off the discomfort pain causes.