Pain and pain relief are caused by two different signaling pathways, but the two pathways are not necessarily independent of one another, according to a study published in Cell Reports.

Researchers from Carnegie Mellon University determined the mechanism by which cellular signals for pain fine-tunes neurons‘ sensitivity to opioids. 

At the neuronal level, when a person experiences pain, a peptide called substance P activates the neurokinin 1 receptor on the neuron’s surface. 

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According to the researchers, when a person takes an opioid to relieve pain, the drug activates a different receptor called the mu-opioid receptor. Once the receptors are activated, they begin a cascade of signals that cause or alleviate pain, and then get internalized into the cell. The mu-opioid receptor has long been a target for pain management drugs, but scientists haven’t been able to figure out how to target the receptor in a way that alleviates pain but doesn’t cause drug tolerance or addiction.

Using a high-resolution fluorescence imaging technique, the researchers visualized cell receptors in live cells and in real time, and demonstrated how pain signals change the rate at which mu-opioid receptors cycle from the cell membrane into the cell and back. 

When activated by DAMGO, an opioid that binds to the mu-opioid receptor and mimics endogenous opioids made in the body, only some of the receptors returned to the cell surface. This mechanism, in part, explains why patients quickly build tolerance to opioids; if the receptors aren’t at the cell surface, the drugs can’t bind to them and enter the cell, the researchers noted.

The researchers then used substance P to activate the pain-causing neurokinin 1 receptor in neurons that had been washed after DAMGO. By administering substance P, they accelerated the rate at which the mu-opioid receptors recycled back to the cell’s surface, indicating that the mechanism could potentially play a role in combating tolerance to opioids.

They found similar results when they substituted fentanyl, a powerful opioid analgesic, for DAMGO.  However, when they substituted morphine, pain did not increase receptor recycling. 

The researchers said in a press release that this may help to explain to why endogenous opioids, fentanyl­­ and morphine cause different responses in our body. In fact, when tolerance to these opioids was measured in a mouse model, substance P significantly reduced the development of tolerance to fentanyl, but not morphine.


1. Shanna L. Bowman SL, et al. Cell Reports, 2015; 10 (11): 1925 DOI: 10.1016/j.celrep.2015.02.045