Spinothalamic Tract
From the dorsal horn neurons, spinothalamic tract (STT) cells carry the information ventral and decussate via the anterior white commissure to the white matter in the lateral and ventrolateral funiculi, which makes up the spinothalamic tract and ascend the spinal cord. STT cells may be sensitive to “high-threshold” input or respond to a variety of thermal, mechanical, and nociceptive input—known as “wide dynamic range” neurons. The axons of the STT cells terminate in a lateral or medial pain pathway. The lateral axons terminate in the posterior ventrobasal thalamic complex (VPL), while the medial axons terminate in the medial and intralaminar thalamus. The lateral pain pathway is responsible for transmitting discriminative information about the location and quality of the pain to the thalamus, primary, and secondary somatosensory cortices. On the other hand, the medial pathway transmits information to the midline brainstem, hypothalamus, amygdala, medial, and intralaminar thalamus which impact the limbic structures to activate the emotional and autonomic responses to pain.2
STT axons also terminate in spinoreticular pathways which impact descending pain pathways, autonomic responsiveness, alerting responses, and limbic responses. The descending pathway can help to balance between facilitation and inhibition of the pain pathway. The subnucleus reticularis dorsalis (SRD) of the dorsal medullary reticular formation plays an important role in this process.
Brain Considerations
The brain does not merely witness the nociceptive signal. It actively participates in constructing the nociceptive signal. The spinothalamic tract ultimately communicates with higher nociception processing centers within the brain. The lateral thalamic nuclei, SI, and SII somatosensory cortices play a sensory discriminative role. The medial thalamic nuclei, and anterior and medial cingulate cortices interpret the emotional significance of the stimuli via the limbic system. The insula, cerebellum, and prefrontal cortex contribute to memory and fear avoidance behaviors. The lentiform nucleus, and cerebellum are involved in reflexive motor responsiveness.2
The limbic system is a set of brain structures on either side of the thalamus that directs emotion, behavior, motivation, long-term memory, and olfaction. The mesolimbic pathway is part of the reward circuit. Dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain project to the forebrain nucleus accumbens (NAc). Burst firing of dopaminergic neurons into the NAc serves as a reward signal and is inhibited by tonic GABA input.15 Opioids inhibit GABAergic tone on these neurons, while pain relief directly engages dopamine circuitry.15 The mesolimbic pathway has been implicated in depression, anxiety, pain sensation, anticipation of analgesia or placebo- induced analgesia, and chronic pain.16 Different types of pain can impact different aspects of the VTA and result in either activation or inhibition. In this way, dopamine release is variable based on various pain signals.16 These dopaminergic pathways are variably altered with stress as well as opioids. Dynorphin and the kappa opioid receptor can play a role in impairing dopamine release in the Na.16
Some are questioning the specificity of particular regions. Some regions may respond preferentially to painful stimulus, but not specifically (or only) to a pain stimulus where actual or potential tissue damage is occurring.17 There are several examples of regions that initially appeared to be specific for nociception, but on further study respond to more generalized input. In one instance, facial pain elicited the activation of a neuron close to SII, but so did a novel or threatening object approaching the visually receptive field.18 In another example, noxious heat produced a response in several neurons in the ACC, but these same neurons were also activated when subjects watched the experimenter receive painful stimuli.19 Care needs to be taken in assigning nociceptive causation to these brain regions. Nevertheless, if neuroimaging is able to identify target brain regions (or more likely patterns of regions) that show increased activity correlated with increased pain intensity, then this neuroimaging may potentially allow' us to predict which interventions might be most impactful to specific groups of people.17
Much of the cortical responses to pain can be modulated with opioid analgesics. In women, more opioid receptors are available in the presence of high estrogen levels.20 Dopamine may also play a role in the pain response. High D2/D3 receptor availability in the striatum is associated w'ith higher pain intensity.21
Cognitive attention to and distraction from stimuli also appear to play a role in the nociceptive processing of pain. During distraction there is an interaction between the anterior cingulate cortex and the frontal cortex. This results in modulation of the PAG and thalamus and decreases activity in the cortical sensory regions, which ultimately results in the decreased perception of pain.22 23
Anticipation of pain also impacts the pain experience. The expectation of pain intensity is necessary for maximal activation of the afferent pain circuitry and maximal perceived pain intensity.2425 It has been suggested that the descending pain pathways are modulated by cognitive suggestions and may impact the system at the dorsal horn of the spinal cord.
The placebo effect has been associated with changes in endogenous opioid release in the prefrontal cortex, anterior cingulate cortex, insula, nucleus accumbens, and ventral striatum.26 The descending pain pathway via the PAG appears to play a role in pain modulation. Not surprisingly, naloxone can block placebo analgesia.27 In a knee arthritis trial, placebo response was noted to correlate with fMRI activity in the right midfrontal gyrus but not in those responsive to duloxetine. Interestingly, in some subjects the duloxetine was able to further activate the placebo response, while in other patients the drug interfered with the placebo response.28
