Working towards designing improved chronic pain medication


Structural data from XRD2 provided important information in understanding a mechanism for specific block of noradrenaline uptake by chronic pain medication with the potential to design better pain medication.

(Ref: Shabareesh P. et al, Nat. Comm. 12, 2199 (2021))

APenmatsa_NatComm_2021
Communication between nerve cells (neurons) happens through the release of chemicals called neurotransmitters. One such neurotransmitter is noradrenaline (also known as norepinephrine), which is important in regulating alertness, arousal and pain sensation. Release of noradrenaline in the spinal cord helps relieve chronic pain conditions like fibromyalgia and neuropathic pain. Increasing the levels of noradrenaline in synapses by blocking its transporter can reduce pain. Hence, drugs that block noradrenaline transport are prescribed as chronic pain medications. In a new study, researchers in the Molecular Biophysics Unit, Indian Institute of Science, led by Aravind Penmatsa used X-ray crystallography to determine the structures of a neurotransmitter transporter to demonstrate how noradrenaline and dopamine – another neurotransmitter –display different types of interactions within the same transporter despite being chemically very similar. The distinct region within the transporter with which noradrenaline interacts is also the site where blockers duloxetine, milnacipran and tramadol, some of
 the popularly prescribed blockers bind and specifically stop noradrenaline uptake. The team discovered that any alterations in this region severely compromise the drugs’ ability to block noradrenaline uptake. The findings provide a paradigm for designing improved inhibitors of noradrenaline transport with limited side-effects, to mitigate chronic pain. The group used several synchrotron beamlines to collect structural data. Two of the six structures in the study were determined from data collected at XRD2, Elettra.


Retrieve Article
Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters,
Shabareesh Pidathala, Aditya Kumar Mallela, Deepthi Joseph & Aravind Penmatsa
Nat. Communications. (2021) 12:2199, doi: 10.1038/s41467-021-22385-9, PDB: 6M38, 6M2R
Last Updated on Tuesday, 11 May 2021 15:48