Modulation of Central Hypersensitivity in Chronic Musculoskeletal Pain by Intravenous Tropisetron

Background

Prolonged afferent nociceptive input induces an increase in the excitability of central sensory neurons. The hyperexcitable neurons amplify the nociceptive signal, thereby producing an exaggerated pain response. This state of central hypersensitivity very likely contributes to pain and disability in patients, even in the presence of limited tissue damage.

The 5-hydroxytryptamine-3 (5-HT-3) receptor is involved in spinal nociceptive transmission. After experimentally induced inflammation, the selective 5-HT-3 receptor antagonist ondansetron inhibited the electrically evoked responses of dorsal horn neurones, but had no effect on these responses in the absence of inflammation. Importantly, the origin of this pathway is a spino-brainstem-spinal loop that includes areas of the brain involved in emotional and affective responses to pain. This suggests that the 5-HT-3 receptors have no significant role under normal conditions, but are activated by peripheral inflammation and contribute to spinal cord hyperexcitability. Their activity could be driven by anxiety and fear.

Spinal cord hyperexcitability elicited by trauma, inflammation or surgery is influenced by descending facilitatory and inhibitory pathways. The periaqueductal grey and endogenous opioid peptides play a central role in the inhibition of spinal cord neuronal responses. Release of enkephalin at supraspinal and spinal levels is evoked by noxious stimulation. Further inhibitory modulation is exerted by serotonergic and noradrenergic systems. These mechanisms may underlie a possible role of psychological disturbances in the spinal cord processing of nociceptive and non-nociceptive stimuli.

While central hypersensitivity mechanisms have been extensively investigated in the animal, data in patients are sparse. In patients, direct measurements at spinal cord or brain neurons can not be made. Therefore, it is impossible to provide direct evidence for neuronal hyperexcitability. However, hypersensitivity can be investigated indirectly by quantitative sensory tests. Typically, hypersensitivity is detected when sensory stimulation evokes pain at stimulus intensities that do not induce pain in normal subjects (lower pain threshold) or when a standardised painful stimulus evokes stronger pain in patients than in normal subjects. Other methods to explore the sensory system are available, but a detailed description is beyond the scope of this section. Whenever pain hypersensitivity is observed after sensory stimulation of healthy areas, its cause must be a hyperexcitability of the central nervous system. Indeed, there is no evidence that peripheral mechanisms could account for a higher pain sensitivity at healthy tissues.