The sensory nuclei of the thalamus, such as the ventral posterolateral (VPL) nucleus, which receives incoming tactile and pain signals, are often referred to as precortical relays. This term seems to imply that the sensory information is simply transferred unchanged to the cortex, where the true work of sensory integration takes place.
But in reality, electrophysiological studies have shown that this is not the case: the signals undergo numerous transformations at each of the connections in the chain of neurons leading from the point where the initial stimulus is received to the cortex. The descending control of pain, which is applied to the various connections in this chain, is a good example of these changes.
ASCENDING PAIN PATHWAYS
What pathways do pain signals follow to perform their protective function? How do these messages reach your brain to tell you which part of your body is hurt? As you might expect for a function as essential as the sensing of pain, the pathways for these signals are numerous, complex, and mutually redundant.
But before we can trace these pain pathways (also known as nociceptive pathways), we must distinguish them from the sensory pathways for non-painful temperature, touch, and proprioception.
These various sensory signals take two different paths to reach the brain, both of which start in a given part of the body and end in the brain’s somatosensory cortex. Each of these paths consists of a chain of three neurons that pass the nerve impulses from one to the next. Where these two paths differ is in the location where they cross the midline in the spinal cord.
Remember that in the human body, the nerves responsible for sensory inputs, as well as those responsible for motor control, are crossed. In other words, the neural pathways from the left side of the body terminate in the right hemisphere of the brain, and vice versa. Hence, at some point in the body, these pathways must cross the body’s midline (in scientific terminology, they must “decussate”).
Now let’s follow the path that any incoming sensory impulse—whether for touch, pain, heat, or proprioception—follows from the spinal cord to the brain. Regardless of the sensory modality, the three neurons in question form a chain running from one side of the spinal cord to the other, and the cell body of the first neuron in this chain is always located in a spinal (dorsal root) ganglion. This neuron is said to be T-shaped, because its axon emerges as a short extension from its cell body and then soon divides into two branches going in opposite directions: one goes to the part of the body that is innervated by this spinal nerve, while the other immediately enters the dorsal root of the spinal cord (an essentially sensory part of the spinal cord, as opposed to the ventral root, which is a motor area). It is from this point on that the two pathways differ.
Adapted from Neuroscience: Exploring the Brain, M.F. Bear, B.W. Connors, and M.A. Paradiso, 2007
The pathway responsible for touch and proprioception is called the lemniscal pathway. The first axon in this pathway runs along the dorsal root of the spinal nerve and up the dorsal column of the spinal cord. (Along the way, this axon also sends out collaterals: branches in the dorsal root that play a valuable role in the local inhibition of pain, among other functions.)
The primary axon, however, remains on the same side of the spinal cord as the side of the body that it innervates (the “ipsilateral” side) until it connects with the second neuron in the chain, which in the case of the lemniscal pathway is located in the medulla. The axon of this second neuron crosses the midline immediately.
It then travels up through the medial lemniscus to the ventral posterolateral (VPL) nucleus of the thalamus, where it connects with the third neuron in the chain.
The pathway that carries information about pain and non-painful temperatures is called the neospinothalamic pathway (or often simply the spinothalamic pathway). The first neuron in this pathway connects to the second neuron not in the medulla, but in the dorsal horn of the spinal cord, on the same side that the nerve impulse comes from.
This second neuron has a single axon, which immediately crosses the midline to the other (contralateral) side of the spinal cord
and goes up to the brain along with the other axons forming the lateral spinothalamic tract. This part of the pathway is described as contralateral, meaning that it runs along the side of the body opposite to the area that its axons innervate.
The axon of the second neuron connects to the third and final neuron of this ascending pathway in the ventral posterolateral (VPL) nucleus of the thalamus.
In both of these pathways, the third neuron sends its axon to the somatosensory cortex, the part of the brain that determines exactly where the original stimulus occurred in the body.
The difference between the routes of the lemniscal pathway (for touch and proprioception) and the spinothalamic pathway (for pain) have special clinical significance, because some injuries that affect only one side of the spinal cord will disrupt only the sense of touch, while others will affect only the sensation of pain.
For example, suppose that the woman in the figure to the right has been injured on the left side of her spinal cord, at the 10th thoracic vertebra. She will experience a reduced sense of touch on the left side of her body below the level of the injury, because the lemniscal pathway runs up the same (ipsilateral) side. She will also experience a reduced sense of pain below the injury, but on the right side of her body, because the spinothalamic pathway runs up the opposite (contralateral) side. As a result of this sensory dissociation, she will be able to feel it when a mosquito lands on her right leg, but not if the mosquito then bites it.
But the incoming nociceptive impulse encounters its very first gate as soon as it enters the dorsal root of the spinal cord. This first relay point in the ascending pathway is thus not just an area through which the nociceptive impulse passes, but rather the first place where it is filtered and integrated with other information.
This first level of integration is referred to as segmental controls of non-pain peripheral origin.
The word “segmental” refers to the fact that this process occurs in each of the segments of the spinal cord corresponding to each vertebra. This segmental control results from the interaction between the nociceptive sensory fibres (A delta and C) and the non-nociceptive ones (A alpha and A beta).
This interaction was modelled in an article, first published in 1962 and then amplified in 1965, that many regard as the most important one ever written on the subject of pain. In this article the authors, Canadian Ronald Melzack and Englishman Patrick Wall, proposed the first model for the endogenous control of pain: the now-famous gate control theory of pain.
This theory posits a special form of connectivity involving not only the sensory input fibres for pain and for light touch, as mentioned above, but also a set of inhibitory interneurons
that are the key element in the authors’ explanation.
As the diagram to the right shows, the nociceptive and non-nociceptive impulses from the body converge at non-specific neurons in the dorsal horn, which project their axons into the contralateral spinothalamic tract. These two types of nerve fibres also communicate with the non-specific neurons through inhibitory interneurons that they contact via collateral fibres. The important difference is the nature of the connection with these interneurons: for the large, non-nociceptive fibres, it is excitatory, but for the nociceptive fibres, it is inhibitory.
It is this particular circuit that forms the virtual gate whose opening and closing will modulate the passage of pain. Under normal conditions, the inhibitory interneurons spontaneously produce action potentials at their own specific frequency. But when the nociceptive fibres
are activated by a pain stimulus, in addition to stimulating the non-specific neuron that projects to the spinothalamic pathway (also known as the “projection neuron”), they also inhibit the spontaneous inhibitory activity of the interneurons, thus depolarizing the projection neuron and increasing the likelihood that it will trigger action potentials.
Another aspect of this circuit’s operation is illustrated by what happens when you hurt yourself and start to rub the injured part of your body vigorously.
This instinctive reaction reduces the sensation of pain by “closing the gate”. The animation below shows how: rubbing your skin activates the sensory fibres for touch, which in turn excite the projection neuron. But these fibres also make numerous excitatory connections to the inhibitory interneurons. As a result, if you keep rubbing your skin, these interneurons will produce a strong hyperpolarization of the projection neuron, thus greatly reducing the probability that it will emit nerve impulses.
Thus we see how it is the relative frequencies of the action potentials in the nociceptive and non-nociceptive fibres that determine how open the “gate” in the spinal cord will be and hence how much pain information will pass through. In addition, there are projections of central origin that can also activate these inhibitory interneurons
in the spinal cord and further close the gate at the segmental level.
Data gathered since 1965 have led to some changes in Melzack and Wall’s original model, but the idea that the perception of pain is modulated from the moment that the pain messages enter the spinal cord remains fundamental to the clinical treatment of pain. For example, it is the origin of clinical applications such as transcutaneous electrical
nerve stimulation (TENS), which produces local analgesia by stimulating the non-nociceptive fibres in the skin.
From an evolutionary standpoint, stress-induced analgesia can be regarded as a component of the fight-or-flight response. It would not be highly adaptive if pain from injuries could prevent us from fighting or fleeing even when our lives depended on it. But once the threat of death has passed, our normal pain-sensing mechanisms have to do their work in order to immobilize the injured part of the body and prevent the injury from getting worse.
Research done on the mechanisms of the descending control pathways for pain since the early 1980s has now given us a better understanding of stress-induced analgesia. We now know that the tendency to experience this phenomenon varies from one individual to another and is influenced by variables such as age, sex, degree of sensitivity to opiates,
and past stressful experiences.
The mechanisms by which stress-induced analgesia inhibits pain seem to involve the descending systems of the midbrain, applying both opioid and non-opioid mechanisms. Research is also tending to show that neurotransmitters associated with stress, such as norepinephrine, and brain structures associated with fear reactions, such as the amygdala,
are also involved. Many other endogenous substances, such as anandamide
and its cannabinoid receptors, also seem to play a role, in this case in the non-opioid effect in the periaqueductal grey matter.