The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 18 No. 3 • July 2015


The results published in a new paper1 will likely be of interest to anybody taking regular NSAID (nonsteroidal antiinflammatory drugs, such as aspirin, Naproxen, or ibuprofen) pain killers, particularly for chronic inflammatory conditions such as arthritis. The researchers report that choline, an alpha7 nicotinic receptor agonist (a natural endogenous activator of this particular type of cholinergic receptor) has anti-nociceptive (anti-pain) effects of its own in a variety of pain models. They were, therefore, interested in a possible positive interaction between choline and aspirin in the treatment of pain and thus carried out experiments with two inflammatory pain models in mice. One of the models they studied was the writhing test, where acetic acid is injected into the lower left quadrant of the abdomen of mice causing what must be excruciating pain as the pain behavior is manifest by writhing and evaluated by the number of writhes. We have chosen not to discuss this gruesome model as the results in terms of the observed pain relief to treatment with choline, aspirin, and a combination of the two were similar to the results of the inflamed paw test, described below.

The other model of pain studied was that caused by subcutaneous carrageenan injection into the paw of a mouse, which caused pain behavior assessed by how long it took the mouse to withdraw its injected paw (the Pain Withdrawal Latency, or PWL) in response to the application of heat; the heat would cause pain to the inflamed paw. The results showed that the administration of a single dose of choline (48 mg/kg, i.v., 1 hour after carrageenan injection) or a single dose of aspirin (30 mg/kg i.v., 1 hour after carrageenan injection) significantly suppressed the carrageenan-produced reduction in PWT only at 2 hours post carrageenan; thus, this time point was used as the test time in the remaining tests. (This is equivalent to less than one serving of our Memory Upgrade III.™) [See]

“Choline (4–48 mg/kg, i.v.) produced a dose-dependent inhibition of carragennan-induced thermal hyperalgesia [pain], which was significant at doses of 16, 24, and 48 mg/kg (F(6,68)=10.8; P<0.01)). Aspirin (0.3125-30 mg/kg) also produced a dose-related inhibition of the carrageenan-induced thermal hyperalgesia, with significant effects at doses of 1.25, 2.5, 10, and 30 mg./kg. (F(5,54)=6.6; P<0.01)).

At low doses, choline (4 and 8 mg/kg, i.v.) or aspirin (0.3125 and 0.625 mg/kg, i.v.) administered alone were reported to have no effect on the carageenan-produced reduction in PWT, but when choline (8 mg/kg) was coadministered with aspirin at 0.6125 mg/kg or choline at 4 mg/kg + aspirin at 0.3125 mg/kg, the combination of drugs significantly reversed the carrageenan reduction of PWT. The effects were observed at 2 hours after carrageenan injection, but also at 3 hours and 4 hours after injection. Hence, the anti-pain effects of the coadministered choline and aspirin was prolonged. (If you wake up with aches in the morning, this mouse dose is equivalent for a human to about one serving of SleepScape™). []

Attempts to Find Mechanisms for the Observed Synergy Between Choline and Aspirin

The authors attempted to identify mechanisms that could help explain the interaction between choline and aspirin (and other NSAIDS).1

Curiously, pretreatment with one alpha 7 nicotinic cholinergic antagonist, MLA, blocked the anti-pain effects of choline, while a different antagonist, alpha-bungarotoxin, enhanced the choline-induced anti-pain effect.1 The researchers propose that the carrageenan-induced hind paw edema in mice is a biphasic event, with an early phase of inflammation resulting from the release of histamine, serotonin, and similar substances, while a later phase is associated with the activation of kinin-like substances. This biphasic behavior may result in different responses to the two alpha-7-nicotinic cholinergic antagonists. Another complication they point out is that choline is a partial agonist of alpha-9 alpha-10 nicotinic cholinergic receptors. “Taken together, the antinociceptive effect of systemic choline seems to be dependent upon the presence of inflammation and its activity may be mainly via attenuating the release of inflammation cytokines through activation with peripheral macrophages and monocytes through alpha-7-nicotinic receptors, but this needs further studies in more pain models.”1

The researchers also note that in their study1 the analgesic effect of choline was inhibited by naloxone, which suggests that opioid receptors are involved in choline’s anti-pain behavior, but that the data from some other studies (for which they provide references) are not consistent with this.

“These results provide support for further study of the synergistic antinociceptive mechanisms of coadministration of choline and NSAIDS such as aspirin, and they provide a basis for exploiting new analgesic treatments using low antinociceptive dose, long antinociceptive course, and reduced side effects.”1

Cholinergic Control of Inflammation May Be a Mechanism for Its Effects on Pain

There has been a considerable amount of research supporting an antiinflammatory function of the cholinergic nervous system.2 One paper3 reported that choline itself, by its signaling via the alpha-7 subunit nicotinic acetylcholine receptor, modulates the release of tumor necrosis factor (TNF), a major proinflammatory cytokine. TNF synthesis and release has been identified in various types of pain.4,5 Blocking TNF-alpha has been very effective in the treatment of rheumatoid arthritis, with sometimes dramatic reductions in both the pain and tissue damage resulting from the disease.6

In a study of the antiinflammatory effects of choline (50 mg/kg, intraperitoneally (i.p.) in mice, this treatment prior to endotoxin (a bacterial cell wall constituent that activates the immune system) administration significantly reduced systemic TNF levels. In the same study, though, mice that did not have alpha-7-nicotinic acetylcholine receptors (knockout mice) did not have reduced systemic TNF levels in response to the same dose of choline, showing that these receptors were required for the reduced TNF (anti-inflammatory) effect of choline. In cells studied by the researchers,3 choline incubation prior to exposure to endotoxin suppressed both TNF and NFkappaB, another major regulatory molecule in inflammation. Choline also suppressed TNF production from endotoxin-stimulated human whole blood and cultured macrophages. As the researchers3 noted, “[t]he effective doses of choline used in the present study (25-50 mg/kg, i.p.) are within the dose range used in [] other studies. It is important to note that we did not observe any adverse neurobehavioral effects of these choline doses, which are comparable with the recommended tolerable upper limit of dietary choline intake in humans.”

Finally, one more curiosity: A paper on the effect of aspirin and opioids on pain was published in the 11 Dec. 1997 Nature;7 the accompanying commentary8 described the findings of the study that the combination of aspirin and opioids is more analgesic than the summed effect of each drug separately with an attempt to identify mechanisms. Here is another example of the difficulty of identifying the pathways of pain regulation. It could link to the choline-aspirin work described above if the analgesic effect of choline is actually inhibited by naloxone (an opioid antagonist).


  1. Yong-Ping et al. Pharmacological action of choline and aspirin coadministration on acute inflammatory pain. Eur J Pain. 15:858-65 (2011).
  2. Rosas-Ballina and Tracey. Cholinergic control of inflammation. J Intern Med. 265:663-79 (2009).
  3. Parrish et al. Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptor-mediated signaling. Mol. Med. 14(9-10):567-74 (2008).
  4. Richter et al. Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats. Arthritis Rheum. 62(12):3806-14 (2010).
  5. Xu et al. The influence of p38 mitogen-activated protein kinase inhibitor on synthesis of inflammatory cytokine tumor necrosis factor alpha in spinal cord of rats with chronic constriction injury. Anesth Analg. 105:1838-44 (2007).
  6. Basbaum et al. Cellular and molecular mechanisms of pain. CELL 139:pg. 275 (2009).
  7. Vaughan et al. How opioids inhibit GABA-mediated neurotransmission. Nature. 390:611-4 (1997).
  8. Williams. The painless synergism of aspirin and opium. Nature. 390:557-9 (1997).

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