Free radicals: cause of ice cream headache and the pain in a triple response?
This is an intriguing problem. Two observations come to mind. The
first was a man in his forties with hypertension who had a coeliac axis
stenosis and who developed abdominal pain whenever he drank cold water
(1). His pain was accompanied by a gastric intramucosal acidosis, which
would appear in my current thinking to be caused by the rate of energy
release by ATP hydrolysis that exceeds the rate at which ATP is
resynthesised by oxidative phosphorylation. Revascularisation eliminated
the the intramucosal acidosis and like the other patients studied appeared
to eliminate his symptoms but these patients are notoriously difficult to
evaluate. Food of course is the usual stimulus. Another investigator has
comfirmed our provocative findings (2).
One mechanism by which intragastric stimuli might cause abdominal
pain is by causing vascular or smooth muscle muscle spasm. Another
mechanism is by causing a steal of blood flow from a midgut supplied by
stenotic mesenteric arteries (3,4,5). Neither of these would seem to
account for an ice cream headache (6). A haematogenous or neural/humoral
reflex needs to be invoked.
A decrease in temperature causes a rise in pH by a purely physical
effect (7). If high enough it will inhibit oxidative phosphorylation by
eliminating the protonmotive force driving ATP resynthesis by oxidative
phosphorylation. In so doing it might increase the [ADP] and induce a
haemotological changes such as activation of the ADP receptors on platlets
(8). Cold is known to cause cryoprecipitation of blood products in some
As the supply of oxygen is not inhibited in these circumstances the
stage may be set for free radical release upon rewarming. In which case a
bolus of free radicals might be released not only into portal venous blood
but also into gastric lymphatics and have direct access to the brain by
draining into the thoracic duct. Perhaps this caused the ice cream
The release of free radicals upon reperfusion has been implicated in
the causation of pain (9). Furthermore the free radical release induced by
reperfusion after a transient fall in gastic intramucosal pH has been
implicated in multiple organ dysfunction (10). Neurological ddysfunction
appears to be the most sensitive symptomatic measure of multiple organ
dysfunction in awake patients(11).
Sir Thomas Lewis brought the scientific method to the investigation
of human disease at the bedside when he was at Univeisty College. In 1927
he described the triple response to a cutaneous njury, flush(redline),
flare(red zone) & weal(edema), and the classic five signs -
rubor(redness), tumor(swelling), calor(Heat), dolor (pain) and loss of
function of inflammation are well known. It starts with dilatation of
blood vessels(vasodilatation) to bring more blood (Hyperemia) and along
with it the mediators of defence & healing. Blood vessels become leaky
allowing escape of fluids(transudation), proteins & cells (exudation)
into tissue space causing edema. The WBC crawl out of
capillary(emigration) towards site of injury attracted by
chemicals(Chemotaxis) and engulf debris (phagocytosis). Antibodies and
other chemical mediators of inflammation serve to neutralise the injurious
agents such as microbes.
If one thinks about cutaneous injury, which contrary to visceral
injury is painful, it occurs in an hyperoxia, hypocarbic environment. This
should inhibit oxidative phosphorylation by elevating the pH and thereby
presumably prevent the generation of free radicals until reperfusion when
it could be excessive. If blood flow is compromised at first from
vasocontriction and platelet plugging coling should also occur compounding
thelevation in pH in increasing the need for an exothermic metabolic
response, one that iappears to occur with anaerobic glycolysis. The lumen
of the gut is, in contrast, microaerophilic. It has a very low pO2,
relative to air, and a pCO2 the same as that in arterial blood or a little
higher on occasions. These are not circumstances in which free radicals
should be produced in anything like the amount presumabky seen after, for
example, removal of a colonic polyp. The difference might account in part
for the difference in pain experienced.
The release of free radicals upon reperfusion might be responsible
for the initial pain experienced in the triple and for an ice cream
headache, the latter being a systemic and the former a local
manifestation. The pain associated with the later inflammatory response
might be a regional manifestation.
If in the evolution of man avoiding the toxic effects of oxygen has
been a crucial property then, thinking in terms of a simple cellular
automata or Wolfram rule(12), pain is a likely derivative. It is not a
response that would have included a nervous system until evolution was
1. Fiddian-Green RG, Stanley JC, Nostrant T, Phillips D. Chronic
gastric ischemia. A cause of abdominal pain or bleeding identified from
the presence of gastric mucosal acidosis.
J Cardiovasc Surg (Torino). 1989 Sep-Oct;30(5):852-9.
2. Faries PL, Narula A, Veith FJ, Pomposelli FB Jr, Marsan BU,
LoGerfo FW The use of gastric tonometry in the assessment of celiac artery
Ann Vasc Surg. 2000 Jan;14(1):20-3.
3. Poole JW, Sammartano RJ, Boley SJ Hemodynamic basis of the pain of
chronic mesenteric ischemia.
Am J Surg. 1987 Feb;153(2):171-6.
4. Boley SJ, Brandt LJ, Veith FJ, Kosches D, Sales C A new
provocative test for chronic mesenteric ischemia.
Am J Gastroenterol. 1991 Jul;86(7):888-91.
5. Fiddian-Green RG. Provocative test for chronic mesenteric
Am J Gastroenterol. 1992 Apr;87(4):543
6. Joseph Hulihan
Ice cream headache
BMJ 1997; 314: 1364
7. JOHN W. SEVERINGHAUS, POUL ASTRUP, and JOHN F. MURRAY Blood Gas
Analysis and Critical Care Medicine. Am. J. Respir. Crit. Care Med.,
Volume 157, Number 4, April 1998, S114-S122
8. Herbert JM, Savi P. P2Y12, a new platelet ADP receptor, target of
Semin Vasc Med. 2003 May;3(2):113-22.
9. Xanthos D, Francis L, Bennett G, Coderre T. Animal Models of
Chronic Pain: Chronic post-ischemia pain: A novel animal model of Complex
Regional Pain Syndrome Type I produced by prolonged hindpaw ischemia and
reperfusion in the rat.
J Pain. 2004 Apr;5(3 Suppl 2):S1.
10. Nielsen VG, Tan S, Baird MS, McCammon AT, Parks DA Gastric
intramucosal pH and multiple organ injury: impact of ischemia-reperfusion
and xanthine oxidase.
Crit Care Med. 1996 Aug;24(8):1339-44.
11. David Taggart
About impaired minds and closed hearts
BMJ 2002; 325: 1255-1256
12. Stephen Wolfram. A New Kind of Science. Wolfram Media, Inc.,
Competing interests: No competing interests