It might be a big family but the pain remains—last chance saloon for selective 5-HT receptor ligands?

The following brief overview reflects our own opinion of where the most likely advances to treating pain (unrelated to IBS and migraine) may come from with respect to ligands directly interacting with specific 5-HT receptors. It is fully appreciated, and possibly more likely, that 5-HT plays a modulatory role in the mediation of analgesic effects of certain compounds, for example tricyclic antidepressants and the newer, safer class of serotonin/noradrenaline re-uptake inhibitors, for example duloxetine and milnacipran. However, we find that recent pre-clinical findings highlight the potential of peripherally acting 5-HT1 and 5-HT2A receptor agonists and centrally penetrating 5-HT7 receptor agonists to reduce chronic pain. We encourage experimentation using human tissues and healthy volunteers to improve the confidence in rationale of targeting such receptors for treatment of pain in humans. However for this to happen the available pharmacological toolbox will also need to be further improved and any safety concerns understood to provide the necessary impetus to go to the clinic.

Research highlights
► The 5-HT receptor family is extensive but the only pain complaint that has yielded to selective modulation of a specific 5-HT receptor is migraine.
► 5-HT may well act effectively against pain when in concert with other neurotransmitter modulators.
► However, recent work suggests certain subtypes of the 5-HT1 receptor family, 5-HT2A receptors and 5-HT7 receptors may have potential as pain therapies.