Role of 5-HT2C receptors in modulating spinal nociceptive processing in neuropathic pain
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Chronic neuropathic pain, as a result of nerve injury or dysfunction in the nervous system, is poorly understood and is usually inadequately treated with analgesics such as morphine. It is characterised by hyperalgesia (an increased sensitivity to a mild noxious stimulus), allodynia (interpretation of a normally innocuous stimulus as noxious) and spontaneous pain (with no precipitating stimulus). Central sensitisation may be due to changes within the central nervous system and particularly the dorsal horn of the spinal cord, which may help to explain the abnormal pain responses observed in humans and animals. Descending inputs from the brainstem can modulate nociception at the level of the spinal dorsal horn and serotonin (5-HT) is one of the neurotransmitters that may be involved. A long-circuited spinal-brainstem-spinal loop can act through 5-HT3 receptors on presynaptic terminals to facilitate afferent nociceptive inputs, especially in models of neuropathic pain. We show that 5-HT2C receptors may also act on dorsal horn neurones involved in nociceptive processing to facilitate their responsiveness. There are conflicting reports of the influence of 5-HT2 receptors in nociception, however there is evidence that activation of spinal 5-HT2A/2C receptors enhances the central transmission of nociceptive signals. Evidence that 5-HT2C receptor mRNA is more abundant in the dorsal horn of the spinal cord than that of any other 5HT2 receptor subtype points to this as a receptor worthy of investigation. We have shown that 5-HT2C and 5-HT2A receptor antagonists attenuate behavioural reflex sensitisation induced by nerve injury or inflammation, with a more marked influence on sensitivity to thermal rather than mechanical stimulation. We also observed delayed development of sensitisation following inflammation or nerve injury in transgenic mice with reduced expression of the 5-HT2C receptor compared to wild-type mice. We have also shown that the expression of the 5-HT2C receptor is increased in the dorsal horn of the spinal cord ipsilateral to nerve injury by immunohistochemical means and we have identified potential binding partners interacting with the carboxy terminal tail of the 5-HT2C receptor in spinal cord extracts. These findings indicate that the spinal 5-HT2C receptor activated by pathways originating in the brainstem may be of importance in contributing to the increased sensitivity to noxious stimuli following nerve injury or inflammatory damage.