IMAGINE the pain of someone holding a burning cigarette to your naked skin.
Now imagine the pain without the cigarette … Imagine a sensation akin to an
electric shock shooting through your shoulder blade. Imagine deep, unremitting
backache that leaves you permanently debilitated. Finally, imagine a skin
sensitivity so acute that even the draft from an open door is painful.
This is the nightmare world of enigmatic pain. Here, the pains that make
people’s lives a misery for decades serve no apparent function. They do not,
for example, warn of potential dangers – of fire, say, or of a twisted ankle –
nor do they ensure that a person slows down and heals an injury. And because
drugs are no use, many sufferers end up doing the rounds from neurologist to
chiropractor to acupuncturist, losing money and gaining little relief. Worse
still, because such pain has no obvious and immediate cause, there is always
the unspoken charge that the pain is imaginary. For some, suicide offers the
only respite.
Advertisement
Nor do doctors escape the anguish. “When a doctor sees the same patient
coming back every few months, and there is nothing [he or shej can do to help
the pain, both the doctor and the patient get desperate,” says Clifford Woolf,
a neurobiologist at University College London. Among themselves, doctors
classify people suffering from this enigmatic, chronic pain as “heartsink”
patients.
Now, an end to at least some of that misery and frustration may be in
sight. Neurobiologists believe that certain diseases and injuries (some of
which are long forgotten by the time the pain becomes a handicap) trigger
crossed wires deep within the nervous system by stimulating the production of
chemicals that encourage nerve growth. Those crossed wires link nerve fibres
carrying everyday messages about touch and pressure from the body’s surface
with the pain pathways to the brain, and they may be at least partially
responsible for triggering the bouts of inexplicable, unpredictable pain.
Painful times
And the recognition that physiology not psychology is to blame is more than
a panacea for the battered egos of patients and doctors. It could also one day
translate into radical new therapies that tackle enigmatic pain both by
attempting to prevent the cross-wiring from occurring in the first place, and
undoing the cross-wiring once it has taken place.
Most pain is vital to survival. The sharp pain associated with, say,
touching a hot iron, is the body’s way of warning that it is under threat.
It’s called protective pain. Signals pass from pain receptors in the skin,
along nerve fibres to the spinal cord, and on to the brain where they provoke
the sensation of pain and, hopefully, evasive action. A second type of pain,
called reparative pain, makes sure that once the damage is done the body gets
a chance to heal. It’s a sickening, aching sensation that is often accompanied
by extreme sensitivity to normal amounts of pressure, heat, or light, and it
only disappears after sufficient time has passed to ensure that the healing
process has got well under way.
Roughly 2 per cent of the population, however, suffer the third, useless
sort of pain that neither acts as a warning nor helps with the healing
process. And this kind of pain costs millions – perhaps billions – worldwide
in lost productivity and healthcare. One estimate set a figure of up to 365
million days of pain in the UK alone.
Studying the mechanisms that underlie inexplicable chronic pain is
difficult in humans, not least because the condition is notoriously variable,
so Woolf and his colleague Richard Coggeshall at the University of Texas
Medical Branch at Galveston turned to the lab rat. The two researchers cut or
crushed the sciatic nerve – a large nerve in the leg that carries information
about touch, temperature, and pain, and relays instructions to the muscles –
of the anaesthetised animals. Then they studied how the nerve fibres in the
rats’ spinal cords changed in response to that type of injury.
In cross section, a darker butterfly-shaped region is imprinted on the
eggshaped spinal cord. The butterfly’s wings are the spinal cord’s ventral and
dorsal horns, the latter of which is divided into five microscopic layers. In
four of the dorsal horn layers, nerve fibres bringing messages about touch
from the skin make contact with the nerve cells that give rise to the massive
nerve tracts that relay the messages on to the brain and other parts of the
spinal cord. The second layer of the dorsal horn, however, is reserved mainly
for incoming nerve fibres relaying pain messages.
Woolf and Coggeshall discovered that within two weeks of the initial
damage, a mass of extra nerve fibres had sprouted into the second layer of the
rat’s dorsal horn. Using an electron microscope to study the connections
between fibres, and electrical recordings to find out what sort of nerve
fibres had encroached on the second layer, the researchers concluded that
there was a massive fifteen-fold increase in the number of touch fibres making
connections with the nerve cells that transmit pain information to the brain,
and that normally only receive inputs from pain fibres.
“Paradoxically, the system that reports on tissue damage [to the brainj, is
itself affected by tissue damage,” says Stephen McMahon, who studies pain at
the St Thomas’s campus of the United Medical and Dental Schools in London.
Woolf thinks it is likely that the same thing happens in patients who have
had a nerve damaged in an accident or by diseases such as diabetes. “There’s a
rewiring so that whenever a fibre is activated by touch or vibration, the
central nerve cells in the spinal cord think they are getting an input of pain
or noxious damage, [and] the person experiences pain,” he says.
Elspeth McLachlan, a pain researcher at the Prince of Wales Medical
Research Institute in Sydney, agrees with Woolf, and points out that the rats’
injuries roughly mimic the sort of damage that often leads to chronic
unexplained pain in a person. Cutting the sciatic nerve is equivalent to
“going through the window in a car crash, and having a great pane of glass cut
through your leg”, she says, and it is just “such injuries that most commonly
precede chronic intractable pain in people”.
The “rewiring” theory also offers clues about why certain surgical
procedures that until recently were fashionable options for people with
chronic pain can actually make the conditions worse. “It suggests that if you
cut a peripheral nerve to relieve pain, you could get central rewiring that
actually causes more pain,” says Coggeshall.
Nerve sprouts
Unexpectedly, the rat results may contain a pleasant surprise for humans:
within nine months, the deviant nerve connections had disappeared. “It was a
tremendous surprise. We had thought that once the whole system had rewired
that was it. But this means it is reversible,” says Woolf. Indeed, in
patients, chronic pain can suddenly disappear of its own accord, suggesting
that what happened in the rats may also happen in humans. But in many cases,
chronic, untreatable pain plagues patients for years on end. For that reason,
Woolf and Coggeshall, together with scientists at Regeneron, a biotechnology
company in Tarrytown in New York state, are now searching for the chemicals
that stimulated the nerve fibres to sprout in the first place because blocking
those chemicals could prevent the development of chronic, purposeless pain in
the first place. They are also looking for any chemicals that might have
helped break the aberrant connections in case they are able to provide a way
of alleviating pain once it has taken hold.
There is already good evidence that a nerve “fertiliser” with the prosaic
name of nerve growth factor, or NGF, triggers a second type of pain-related
crosswiring in which sympathetic nerves, whose task it is to regulate organs
like the heart, blood vessels, and stomach, connect to the types of nerve
fibres that carry touch information to the spinal cord.
McLachlan and Wilfred Ja¨nig at the University of Kiel in Germany
looked at
the sympathetic nerves of rats with cut sciatic nerves. They found that in
damaged animals, the sympathetic nerves that usually just control the blood
vessels send out shoots that encircle the cell bodies of the touch nerves
clustering in knots called ganglia just outside the spinal column. In
McLachlan’s rats, not only were the two types of nerves connected by the
sprouts, but when the sympathetic nerves were stimulated with electricity, the
touch fibres responded by becoming either more or less active. Because those
touch nerve fibres are the very same ones that Woolf and Coggeshall discovered
encroaching on the pathways in the spinal cord that relay pain information to
the brain, it seems likely that nerve impulses passing along sympathetic nerve
fibres may also trigger enigmatic pain, says McLachlan.
At roughly the same time as McLachlan was making her discovery, Brian Davis
and Kathryn Albers at the University of Kentucky in Lexington were genetically
engineering mice to produce too much NGF in their skin in an effort to find
out how the chemical regulates the development of the nervous system in a
growing animal.
The effects of the extra NGF turned out to be dramatic and surprising. Not
only are the engineered mice extremely sensitive to the pain of having their
feet poked with a nylon fibre, their nervous systems are wired to the same
strange plan as McLachlan’s rats. NGF is secreted by the stumps of damaged
nerves, so it is likely that the chemical also triggers the sprouting of the
sympathetic nerves in the rats with cut sciatic nerves.
In the case of the engineered mice, says Davis, the ends of the sensory
nerve fibres pick up NGF in the skin and transport it to their cell bodies,
where presumably it leaks out and stimulates the growth of the nearby
sympathetic nerves. “At the moment, we don’t know whether the NGF keeps going
into the spinal cord,” he explains. But if it does, NGF would also be
implicated in forging those mysterious connections discovered by Woolf and
Coggeshall.
The discovery that pain, nerve damage, nerve fertilisers, and the rewiring
of the nervous system are inextricably linked in animals has brought a new
impetus to pain research, says McMahon. He is careful to add a rider that
animal studies have also linked chronic pain to a range of other
abnormalities, including changes in the pain receptors in the skin, in the
nerve fibres that transmit the pain messages from the body’s surface, and in
the chemicals that transmit messages from one nerve cell to the next. “It’s
not yet clear which is the most significant in terms of pain sensation for the
patient,” says McMahon.
But despite the unknowns, there is enough evidence about nerve rewiring for
researchers and doctors to start devising new strategies for combating this
purposeless pain. Traditionally, doctors treat severe pain with opiate-like
drugs. However, even although these drugs hamper the transmission of pain
messages in the spinal cord, they are no use for people suffering from the
wrong sort of pain. Now, they can start hoping for drugs that will either
block the production of NGF and other nerve fertilisers immediately following
a severe injury at the actual sites where rewiring is likely to occur or that
will undo the rewiring once it has happened. “It’s a long way down the line,”
says McLachlan; “but now it is conceivable.”
Meanwhile, for those tortured by what once seemed to be entirely
inexplicable pains, there is at least the comfort of knowing that it’s their
nerve cells – not their minds – that have gone haywire.