Does Tylenol Exert its Analgesic Effects via the Spinal Cord?

What do we (not) know about how paracetamol (acetaminophen) works? (Toussaint et al., 2010)

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From the beginning, the focus of the search for paracetamol’s analgesic mechanism has concentrated on the central nervous system. When administered intraventricularly [i.e., directly into the ventricular system of the brain], acetaminophen produces no significant analgesia (115, 132). This finding lead to attempts to inject acetaminophen into the spinal cord (i.t.), which produced marked dose-related antinociception (132).

Yesterday’s post about Tylenol as a cure for mortality salience and existential dread got me a little worked up. The first author’s public endorsement of acetaminophen as a possible treatment for chronic anxiety disorders was too much to handle (along with the less than stellar experimental rigor). Is watching a 4 min clip of a David Lynch film really the same thing as a clinically diagnosed psychiatric disorder (Randles et al., 2013)? Why Tylenol and not other pain relievers? What is the hypothesized mechanism of action? Wouldn’t we already know by now, from epidemiological studies at the very least, if Tylenol was an effective anti-anxiety medication?

So I started wondering about acetaminophen's actual mechanism of action. I was quite surprised that it's somewhat mysterious. Randles et al. cited one paper on this:

Second, acetaminophen affects a number of brain regions, some of which are not directly related to physical or social distress (Toussaint et al., 2010).

This led me to believe there was evidence from human neuroimaging studies. Turns out there isn't, beyond the Dewall et al. (2010) paper, which states:

Although the precise mechanisms by which acetaminophen exerts an analgesic effect are still unclear, it is widely accepted that acetaminophen reduces pain through central, rather than peripheral, nervous system mechanisms (Anderson, 2008; H.S. Smith, 2009).

I would like to point out that the spinal cord is part of the central nervous system. So if it's really true that acetaminophen exerts its pain-relieving effects through synapses in the spinal cord, then what does this say about providing relief from the angst of social exclusion, mortality salience, and existential dread? That it's based on nociceptive spinal cord neurons in laminae I, II, and V? For a visual illustration of this pathway, I highly recommend viewing the animation, Dissection of DLF blocks analgesia, at Neuroscience Online.

One hypothesis is that Tylenol (acetaminophen) may act on descending serotonergic pathways (purple projection) at the level of the spinal cord (red synapses). Figure modified from Neuroscience Online.


However, it's not that simple. The review paper by Toussaint et al. (2010) concluded, "No one mechanism has been definitively shown to account for its analgesic activity." For its proposed mechanisms of action, they presented evidence both for and against Cyclooxygenase (EC 1.14.99.1, COX) inhibition, COX-1, COX-2, 'COX-3', peroxidase, nitric oxide synthase, cannabinoid receptors, and of course serotonin:

There is substantial evidence that paracetamol’s mechanism of analgesia in some manner involves the descending serotonergical pathway. 5-HT neurons, largely originating in raphe nuclei located in the brain stem (117, 118) send projections down to the spinal cord that synapse on afferent neurons entering the spinal cord. These descending projections exert an inhibitory (analgesic) effect on the incoming pain signal before it is transmited to higher CNS centres.

Note that these are not the same serotonergic pathways often implicated in depression. The terminal synapses for the latter are indeed located in the brain and not the spinal cord.

Last night, in real life, I followed the Watertown news live via @sethmnookin and @taylordobbs (like many others).

This morning I dreamt that my workplace had transformed into an institutional fortress taken over by a gang of murderous criminals. The actual law enforcement authorities were too busy watching television talk shows to do anything about it. The thugs were threatening and torturing and killing people in the building. I managed to escape down a balcony exit and hid out for a while, avoiding detection but fearful that the thugs would find me and kill me. They were unstoppable, and there seemed to be no way out. I informed an old West-style sheriff, who managed to detain a carload of the evildoers. While continuing to hide, I wondered whether I would be able to shoot them all dead with a fully automatic weapon before they shot and killed me.

Then an early morning doorbell rang and woke me up. It was an unexpected FedEx delivery. In my barely awake state, I thought it might be a bomb.

Why am I telling you all this?? Because I find it very hard to believe that Tylenol, a drug that's relatively ineffective for my own headache pain, could possibly alleviate the anxiety caused by this nightmare. Or by the real life nightmare that's affected so many people in Boston.


References

Dewall CN, Macdonald G, Webster GD, Masten CL, Baumeister RF, Powell C, Combs D, Schurtz DR, Stillman TF, Tice DM, Eisenberger NI. (2010). Acetaminophen reduces social pain: behavioral and neural evidence. Psychol Sci. 21:931-7.

Randles, D., Heine, S., & Santos, N. (2013). The Common Pain of Surrealism and Death: Acetaminophen Reduces Compensatory Affirmation Following Meaning Threats. Psychological Science DOI: 10.1177/0956797612464786

Toussaint, K., Yang, X., Zielinski, M., Reigle, K., Sacavage, S., Nagar, S., & Raffa, R. (2010). What do we (not) know about how paracetamol (acetaminophen) works? Journal of Clinical Pharmacy and Therapeutics, 35 (6), 617-638 DOI: 10.1111/j.1365-2710.2009.01143.x