In addition to the peripheral and spinal mechanisms discussed, supraspinal mechanisms are thought to play an important role in neuropathic pain.173,174 The periaqueductal gray (PAG) is the most characterized part of a CNS circuit that controls nociceptive transmission at the level of the spinal cord.175 The PAG integrates inputs from areas such as the limbic forebrain, diencephalon, amygdala, and hippocampus with ascending nociceptive input from the dorsal horn176 and is therefore associated with the affective and autonomic responses to pain.
The PAG is closely associated with the brainstem including the rostral ventromedial medulla (RVM), and is critical in the descending modulation of spinal activity through monoaminergic and other pathways.177 Likely via anatomically distinct pathways, the PAG and RVM can exert both facilitatory and inhibitory influences on the spinal cord.178 The balance of these two supraspinal pathways and primary afferent input, ultimately determines the excitability of spinal neurons.174 Under pathological conditions, enhancement of descending facilitatory controls to the spinal cord are likely to allow excitatory influences to predominate to maintain spinal central sensitization (Figure 1.8).
Facilitatory cells within the RVM are classed as ON cells, whereas cells that have inhibitory influences on the spinal cord are termed OFF cells.179 Following nerve injury, there is enhanced descending excitatory drive from the RVM180 which may represent a central compensatory mechanism for the loss of normal sensory input following peripheral nerve damage.174 The brainstem areas involved are also implicated in autonomic responses, emotions, and sleep. Therefore, these same pathways likely underpin the well-established links between these states and pain, and may provide a basis for an affective component of pain.181
Various transmitter pathways are implicated in descending control mechanisms. For example, CCK, an antianalgesic peptide, may contribute to RVM neuron excitability.182 Intra-RVM CCK produces reversible thermal and tactile hypersensitivity in naive rats141 and prevents both the activation of OFF cells and the antinociception produced by systemic morphine.183 Additionally, although thought mainly to play an inhibitory role in supraspinal systems,184 supraspinal ser-otonergic inputs to the spinal cord originating in the RVM may play a role in facilitatory influences following peripheral nerve injury.185 The 5HT3 receptor, localized to a novel group of small diameter afferents, and a larger
Fear, anxiety, sleep, autonomic changes
Figure 1.8 Overview of supraspinal involvement in neuropathic pain. Peripheral nerve injury induces spontaneous ectopic activity at the site of injury and the dorsal root ganglion (DRG) resulting in increased release of glutamate and neuropeptides (such as substance P) to the spinal cord, thereby promoting sensory transmission in the spinal cord. Centrally, there is increased function of the N-methyl-D-aspartic acid (NMDA) receptor and enhanced descending activity from the rostral ventromedial medulla (RVM) serotonergic excitatory pathways. All these mechanisms can contribute to the development of abnormal pain accompanying nerve injury. Plasticity is seen in the expression and function of ion channels (e.g. Na1 channels) and neurotransmitters (e.g. substance P). Sprouting of sympathetic nerve fibers in the DRG act to sensitize peripheral afferents. Adapted from Suzuki and Dickenson, 20 05,174 by permission of S Karger AG, Basel.
number of presumed A-delta afferent fibers, has been implicated as the target receptor of this system. Ondan-setron, a 5HT3 antagonist exerts influences particularly on punctate mechanical responses after nerve injury.187 Additionally, a preliminary clinical study suggests that block of 5HT3 receptors has clinical utility in the treatment of pain.188
Finally, evidence suggests that cannabinoids produce their antinociceptive effect at least in part by recruiting the PAG-RVM modulatory system.189 CB1 receptors are densely expressed in the PAG, and microinjection of CBj agonists into the PAG or RVM produces antinocicep-tion.190 CB1 receptors are also known to be expressed on rostrocaudally directed fibers in the dorsolateral funicu-lus, a major tract for descending control systems.169,170
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