Letter: The natural analgesic conolidine targets the newly identified opioid scavenger ACKR3/CXCR7

[nerd]

Szpakowska, M., Decker, A.M., Meyrath, M. et al. The natural analgesic conolidine targets the newly identified opioid scavenger ACKR3/CXCR7. Sig Transduct Target Ther 6, 209 (2021). doi: 10.1038/s41392-021-00548-w

Authors: Martyna Szpakowska, Ann M. Decker, Max Meyrath, Christie B. Palmer, Bruce E. Blough, Ojas A. Namjoshi & Andy Chevigné

The atypical chemokine receptor ACKR3 has recently been reported to act as an opioid scavenger with unique negative regulatory properties towards different families of opioid peptides. Here, we show that conolidine, a natural analgesic alkaloid used in traditional Chinese medicine, targets ACKR3, thereby providing additional proof of a correlation between ACKR3 and pain modulation and opening alternative therapeutic avenues for the treatment of chronic pain.

While conolidine was shown to bind to serotonin-3 ion channel, the norepinephrine transporter, N-type Cav2.2 calcium channels, as well as several GPCRs including the α2B adrenergic (ADRA2B), α2C adrenergic (ADRA2C), and histamine-2 (HRH2) receptors,5 the low affinity of these interactions suggests that they do not mediate the primary mechanism of action of conolidine.

 

[nerd]

I wonder if Naltrexone might also have this mechanism, or if Naltrexone has the Cav2.2 mechanism. I think there is the possibility that different affinities to different opioid receptors lead to a targeted activation of specific opioid receptors only when applied in low doses.

 

[katabasis]

That's neat - based on the description, an ACKR3 antagonist like conolidine might end up doing something similar to endorphinase/enkephalinase inhibitors, increasing the concentration of endogenous opioids. Though I wonder whether preventing the ACKR3 from scavenging CXC chemokines like IL-8 might also cause a pro-inflammatory effect.

I wonder if Naltrexone might also have this mechanism, or if Naltrexone has the Cav2.2 mechanism. I think there is the possibility that different affinities to different opioid receptors lead to a targeted activation of specific opioid receptors only when applied in low doses.

I was always under the impression that the majority of naltrexone's effect when used as LDN was due to its antagonism of TLR4, and that its affinity for opioid receptors was too low at that dosage to contribute much. I would love to see a ACKR3 binding assay done for naltrexone and many other opioid compounds now that we know they're relevant, though.

 

[nerd]

I was always under the impression that the majority of naltrexone's effect when used as LDN was due to its antagonism of TLR4

For CFS/ME, the TLR4 pathway modulation is probably a major mechanism of action. But I've also read reports on its use for chronic pain, and why this can alleviate pain without a significant interaction with opioid receptors isn't resolved yet.