Pain Pathways

The current model of descending pain modulation involves both inhibitory and facilitatory influences on spinal nociceptive transmission. The balance between inhibition and facilitation is dependent on different behavioral, emotional, and pathologic conditions. Intense stress or fear is associated with decreased response to pain, whereas inflammation, nerve injury, or sickness is associated with hyperalgesia that partially can be ascribed to descending facilitatory mechanisms. Several studies suggest that descending facilitatory systems are also activated by safety signals that follow an aversive event. In addition, descending facilitation of spinal nociception contributes to central sensitization and development of secondary hyperalgesia. Finally, hyperalgesia encountered during acute opioid abstinence also entails descending nociceptive facilitation from the rostral ventromedial medulla.

A number of supraspinal sites activated by nociceptive input contribute to central modulation of pain. The most prominent ones include periaqueductal gray (PAG) and rostral ventromedial medulla (RVM). The effects of descending modulation are exerted in the spinal dorsal horn on the synapse between the primary afferent and projection neurons or on interneurons that synapse with projection neurons, by inhibiting the release of neurotransmitter from primary afferent fibers or by inhibiting the function of neurotransmitter receptors on the postsynaptic neuron.

In awake, behaving animals, anterolateral periaqueductal gray (PAG) stimulation leads to immobility, sympathoinhibition, and analgesia as well as inhibition of nociceptive dorsal horn neurons, including spinothalamic tract cells. The PAG contains a large number of neurons. Local injection of opioids, nonspecific enkephalin, substance P, and gamma-aminobutyric acid (GABA)ergic excitants or neuropeptides into the PAG produces analgesia in animals. Excitatory pathways projecting from the PAG to the brainstem are subject to inhibitory control by GABAergic inhibitory neurons within the PAG. Analgesic opioids and cannabinoids relieve GABAergic control and thus induce analgesia. The PAG is significantly interconnected with the hypothalamus and limbic forebrain structures, including the amygdala. This suggests that cognitive and emotional aspects influence ascending nociceptive input, further modulating the resultant experience of pain.

Major brainstem inputs to the PAG originate from the nucleus cuneiformis, the locus ceruleus, the pontomedullary reticular formation, and other catecholaminergic nuclei.

Major descending projections from the anterolateral PAG are to the rostral ventromedial medulla, including the nucleus raphe magnus and adjacent reticular formation. The PAG pain-modulating action is relayed almost exclusively through the RVM that, in turn, sends bilateral descending projections through posterolateral spinal funiculi terminating within the spinal dorsal horn. The RVM is a functional term describing the midline pontomedullary area in which opioid injection or electrical stimulation produces antinociception, that is, analgesia. It includes the nucleus raphe magnus and adjacent reticular formation and projects diffusely to dorsal horn laminae important in nociceptive processing, including superficial layers and deep dorsal horn.

With increasing understanding of RVM neuronal physiology, it is recognized that this area is central to the mediation of the bidirectional control of nociception. It receives projections from serotonin-containing neurons of the dorsal raphe, neurotensinergic neurons of the PAG, and limbic and prelimbic cortex, including the anterior insula. Nonselective stimulation or inactivation of RVM neurons can either suppress or facilitate nociception, depending on the functional background. This suggests that there are parallel inhibitory and facilitatory output pathways from the RVM to the spinal cord. Adjacent neurons are simultaneously under facilitatory and inhibitory control from supraspinal structures. The equilibrium between inhibition and facilitation determines the net effect of descending modulation on nociceptive transmission.

The RVM includes three distinct types of neurons: (1) neurons that begin discharging just before the withdrawal from noxious heat, entering a period of activity (“ON-cells”), (2) neurons that stop discharging before the withdrawal reflex, entering a period of silence (“OFF-cells”), and (3) neurons that do not demonstrate consistent changes in activity when withdrawal reflex occurs (“neutral cells”). ON and OFF cells send projections specifically to laminae I, II, and V of the dorsal horn. Activation of OFF cells produces behavioral antinociception, and is required for the analgesic opioid effect. In contrast, direct, selective activation of ON cells produces hyperalgesia; their discharge is associated with enhanced nociception. Thus OFF cells exert a net inhibitory effect on nociception, whereas the ON cells play a facilitatory role in the descending modulation of pain.

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