Phd in PHARMACOLOGY AND TOXICOLOGY

Thesis title: The Role of Cinnabarinic Acid in the Central Nervous System

Cinnabarinic acid (CA), a kynurenine pathway metabolite, is a pleiotropic molecule whose function is only partially elucidated. CA behaves as an orthosteric agonist of mGlu4 receptors and is found in very low amount in the CNS but, in neuroinflammation conditions it dramatically increases. CA can also interact with aryl hydrocarbon receptor (AHR), a transcription factor of several genes and known for its ability to bind arylic xenobiotics. Evidences supports the involvement of the kynurenine pathway in the regulation of pain thresholds and in pathophysiology of chronic pain. In the present study we found that CA has an analgesic effect at low doses in the formalin test, while the effect tended to disappear at high doses. CA did not show analgesic activity in mGlu4-/- mice confirming his affinity for these receptors, but the analgesic activity persisted even in mice pretreated with the blockade of AHR. In the CCI model, a single administration of CA was able to increase the mechanical thresholds with a time curve comparable to its passage into the brain and showing anti allodynic properties. Action that disappeared in chronic treatment. We also observed an increase in pain thresholds in animals treated for seven days with CA in presence of AHR antagonist. In the CCI model, the in vivo recording of secondary order sensory neurons in the dorsal horn of the spinal cord showed that a single injection of CA had no effect on the firing rate, frequency of excitation, and duration of excitation of nociceptive neurons but largely reduced all three parameters in the presence of locally applied AHR antagonist, and increased all parameters in the presence of the mGlu group III antagonist. In the ON neuron of the RVM recordings where AHR blockade or mGlu group III antagonist were locally applied in the PAG showed a similar scenario of spinal cord recordings except of a reduction in the frequency and duration of excitation when CA was administered alone. In chronic treatment the combined administration with CA and AHR antagonist reduced all parameters observed in CCI mice treated with vehicle. In the same conditions the analysis on the ON cells of the RVM, showed similar data to that observed in the spinal cord with the exception of a significant reduction in the firing rate of ON neurons observed with CA alone. Finally, CA in terms of nociception is working through mGlu4 receptors mainly, at least in the antinocifensive properties. CA has antiallodynic effect but it’s effect is stronger when the AHR is blocked. These observations, taken together, increase the pool of knowledge on the kynurenine present in trace amounts of cinnabarinic acid and contribute to the elucidation of its endogenous role in the CNS in physiological or pathological conditions.