Dynorphin A

Where it comes from

Made in

Hypothalamus, striatum, hippocampus, spinal cord dorsal horn, and the KNDy neurons

Sent out by

Stress, pain and drugs of abuse; the kappa system is the brain’s counterweight to reward

Acts on

• Kappa receptors in reward circuits, amygdala and spinal cord
• Vasopressin neurons
• KNDy neurons (the brake on GnRH pulses)

What it does

• Produces dysphoria and aversion, the low after the high and part of withdrawal and depression ¹
• Relieves pain through kappa receptors at low doses, and at high doses in the injured spinal cord worsens it through NMDA receptors
• Slows the GnRH pulse generator

In medicine

• Kappa agonists treat itch: nalfurafine, approved in Japan in 2009 for the itch of dialysis, and difelikefalin (2021), which stays outside the brain, for the itch of haemodialysis ²³
• No medicine copies dynorphin itself, and spinal fluid dynorphin is a research measurement rather than a test

Beyond the body’s own use

• Difelikefalin halved the itch of haemodialysis in about one patient in two over twelve weeks against about three in ten on placebo, which is the clearest evidence that the kappa system can be used without reaching the brain ²
• Kappa blockers were taken into phase 3 for depression with loss of pleasure and did not work: the aticaprant programme was stopped for want of effect, and navacaprant missed in three trials ⁴
• Salvinorin A, from the sage Salvia divinorum, is a kappa agonist, which is why its effects are dysphoric and strange; it is controlled in several countries and is a medicine in none