Issues
Serotonergic metamodulation of mGlu2/3 receptors, a new mechanism for pain management: the case of trazodone
Trazodone (TZD) is commonly used for depression and insomnia and the likely effect accounting for its antidepressant activity is its antagonistic action at serotonergic receptors, particularly the 5-HT2A receptors. However, emerging evidence supports the application of TZD for the management of chronic pain. Several cellular events are potentially involved in its antalgic activity, and, among them, there is the metamodulation linking 5-HT2A and mGlu2/3 receptors in spinal cord glutamatergic nerve endings. The term “metamodulation” refers to the integration of the neuronal signal involving colocalized receptors functionally and even physically associated. These receptors can influence each other, finely tuning the efficiency of synaptic transmission.
The aim of this review is to analyze the data from both in vitro and in vivo preclinical studies proving the existence and the functional interaction linking 5-HT2A and mGlu2/3 receptors. The review then focuses on the maladaptation of this metamodulatory interaction in the spinal cord of animals suffering from sciatic ligation and finally describes the impact of TZD on the 5-HT2A-mGlu2/3 metamodulation in both physiological and pathological conditions.
In this context, new unpublished results from in vivo preclinical studies in a chronic constriction injury rat model of neuropathic pain are provided which confirm the analgesic effect of TZD on mechanical hyperalgesia and spontaneous pain in these rats.
In conclusion, in a whole the data unveil a cellular mechanism that could subserve the analgesic activity of TZD and support its use in clinic for pain management.
Impact statement
The 5-HT2A antagonist trazodone is a potent metamodulator of the spinal mGlu2/3 autoreceptors and recovers their efficiency in controlling glutamate exocytosis, supporting its use for the management of pain.
