Antidepressants Just Don’t Work on Descending Inhibition

Neurobiol Dis. 2013 Dec;60:39-50.Antidepressants suppress neuropathic pain by a peripheral β2-adrenoceptor mediated anti-TNFα mechanism.
Bohren Y, Tessier LH, Megat S, Petitjean H, Hugel S, Daniel D, Kremer M, Fournel  S, Hein L, Schlichter R, Freund-Mercier MJ, Yalcin I, Barrot M.

  • lesion of central descending noradrenergic pathways does not block painkilling effects of Nortriptyline – It was always thought descending “endorphin-like” response was its effect but that should not happen with damage to DNIC
  • the fact damage to peripheral sympathetic NS blocks nortriptyline response suggests its effects as more β2-adrenoceptors related.  It is though this effect on the nervous system blocks cytokine TNF production.
  • It is thought to be a noradrenergic effect so drugs like venlafaxine and duoxetine should be useful. Interestingly, oral asthma drugs like terbutaline (bricanyl) could also be helpful.
  • Comment – will the future involve taking nortriptyline and terbutaline combined to block TNF production?

Dr. Serge Marchand of Sherbrooke when asked about this study, stated there lesion were not accurate so results were not accurate. It seems that another group has taken a crack at knocking out the DNIC circuit to see if amitriptyline will still work:

Anesth Analg. 2017 Oct;125(4):1281-1288. doi: 10.1213/ANE.0000000000002352.
Repeated Administration of Amitriptyline in Neuropathic Pain: Modulation of the
Noradrenergic Descending Inhibitory System.
Hiroki T et al

  • suppression of noradrenergic descending inhibitory systems by chemically knocking out noradrenergic neurons in the locus coeruleus (LC) and spinal cord.
  • amitriptyline [still] produced antihyperalgesic effects against neuropathic pain despite suppression of noradrenergic descending inhibitory systems. Amitriptyline activated LC [locus coeruleus] neurons and increased noradrenergic fibers density in L5 spinal nerve ligation (SNL) rats.
  • this analgesic effect was not reversed by the α2-adrenoceptor antagonist so put in doubt first article’s idea its related to α2-adrenoceptors
  • does find that serotonin and noradrenaline reuptake inhibitors and gabapentinoids require normal descending noradrenergic inhibition.

Comment: – does look like amitriptyline will augment SNRI and gabapentinoids as they have differing effects golden goose pas cher golden goose pas cher

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