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Mechanisms of pain

Article in Proceedings of the National Academy of Sciences · November 2001

DOI: 10.1073/pnas.211373398 · Source: PubMed

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From the Academy

Mechanisms of pain
Cheryl L. Stucky*†, Michael S. Gold‡, and Xu Zhang§
*Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226; ‡Department of Oral and Craniofacial
Biological Sciences, University of Maryland, Baltimore, MD 21201; and §Institute of Neuroscience, Shanghai Institute of Life Sciences,
Chinese Academy of Sciences, Shanghai 200031, China

Persistent or chronic pain is the primary reason people seek medical care, yet current therapies are either inadequate for certain types
of pain or cause intolerable side effects. Recently, pain neurobiologists have identified a number of cellular and molecular processes that
lead to the initiation and maintenance of pain. Understanding these underlying mechanisms has given significant promise for the
development of more effective, more specific pain therapies in the near future.

Persistent Pain Is a Major Public Health Problem Today properties of neurotransmitters, receptors, and ion channels can
ultimately result in increased functional activity of neurons in the
O ver one-third of the world’s population suffers from persistent
or recurrent pain, costing the American public alone approx-
imately $100 billion each year in health care, compensation, and
pain pathway. Conversely, plasticity can decrease the body’s own
pain inhibitory systems, resulting ultimately in increased pain.
litigation (1). Chronic pain is associated with conditions such as Injury, inflammation, and disease can all cause neuronal plasticity
back injury, migraine headaches, arthritis, herpes zoster, diabetic and increased pain by means of increased excitatory or decreased
neuropathy, temporomandibular joint syndrome, and cancer. Many inhibitory mechanisms. Plasticity can result in short-term changes
of the currently available pain therapies are either inadequate or that last minutes to hours, or long-term changes which may be
cause uncomfortable to deleterious side effects. Chronic pain permanent.
results not just from the physical insult but also from a combination Why Focus on the Primary Afferent Neuron?
of physical, emotional, psychological, and social abnormalities.
Pain transduction and perception is extensive and complex, involv-
Because many pains persist after an insult is healed, the ongoing
ing fundamental biological events at multiple levels of the nervous
pain rather than the injury underlies the patient’s disability. Un-
system (Fig. 1). Our Frontiers of Science session was not intended
treated pain may become self-perpetuating because pain has im-
to be a comprehensive review of the latest findings at all levels of
munosuppressive effects that leave patients susceptible to subse-
the pain pathway. Instead, we focused on the place where sensation
quent diseases. It is now clear that if we can effectively treat the pain
of pain is initiated, the primary afferent nociceptor. Nociceptors are
despite the underlying cause, it will be possible for patients to regain
a subpopulation of primary sensory neurons that are activated by
normal functioning. The key to more successful pain treatment is
‘‘noxious’’ stimuli, i.e., stimuli that can produce tissue damage.
to understand the mechanisms that generate and maintain chronic
Compelling evidence suggests that plasticity in nociceptors contrib-
pain.
utes substantially to the increased pain one feels in the presence of

FROM THE
ACADEMY
Why Is Pain a New Frontier of Science? injury. Plasticity in nociceptors is critical for both the development
The onset of the 21st century is an incredibly exciting time in pain and maintenance of plasticity in the central nervous system (2).
biology. Information from recent studies in basic pain research is That many receptors and ion channels recently identified are
virtually exploding and has revealed numerous novel targets for the found specifically in nociceptors makes these proteins very good
advent of new pain therapies. Major advances have occurred at targets for eliminating pain without inducing side effects. Finally,
levels spanning from molecular studies that have identified trans- the accessibility of the peripheral nervous system makes noci-
duction proteins in nociceptors to cortical imaging studies which ceptors a logical target for the development of novel therapeutic
reveal how pain is experienced on a cognitive level (2, 3). Two key interventions.
lines of discovery have been (i) molecular兾cellular transduction Do Specific Types of Nociceptors Mediate Different
mechanisms and (ii) neuronal plasticity. Types of Pain?
Molecular兾Cellular Mechanisms Nociceptors are extremely heterogeneous, differing in the neuro-
Elegant molecular genetic studies conducted in the past few years transmitters they contain, the receptors and ion channels they
have now enabled us to identify specific molecules that are involved express, their speed of conduction, their response properties to
in the processes of pain transduction. A giant step forward came noxious stimuli, and their capacity to be sensitized during inflam-
with the identification of proteins called vanilloid receptors, which mation, injury, and disease. Significant progress toward alleviating
allow us to detect noxious heat (4, 5). The VR1 protein is a heat pain will occur if we are able to achieve the following goals: (i)
transducer because it converts thermal energy into an electrical determine the function of these different subpopulations of noci-
signal (action potentials) that is sent to the central nervous system, ceptors, (ii) determine whether specific subpopulations mediate
enabling us to detect a stimulus as painfully hot. Without the VR1 distinct types of pain, and (iii) identify what cellular and molecular
receptor, one does not effectively detect noxious heat, particularly targets are altered on specific populations of nociceptors during
in the setting of inflammation (6, 18). Recently, basic pain research- different types of pain. Ultimately, these aims will allow the
ers have identified a number of transduction molecules that will
clearly be key targets in developing pioneering pain therapies (7).
This paper is a summary of a session presented at the third annual Chinese–American
Neuronal Plasticity Frontiers of Science symposium, held October 20 –22, 2000, at the Arnold and Mabel
Plasticity is a term used to refer to changes that occur in the Beckman Center of the National Academies of Science and Engineering in Irvine, CA.
established nervous system. Changes in neuronal structure; con- Abbreviations: IB4, isolectin B4; CCK, cholecystokinin.
nections between neurons; and alterations in the quantity and †To whom reprint requests should be addressed. E-mail: [email protected].

www.pnas.org兾cgi兾doi兾10.1073兾pnas.211373398 PNAS 兩 October 9, 2001 兩 vol. 98 兩 no. 21 兩 11845–11846

 neuropeptides but expresses a surface carbohydrate group that
selectively binds to a plant lectin called isolectin B4 (IB4). This
subpopulation of neurons is supported by glial-derived neurotro-
phic factor during early postnatal development (9, 10). The IB4-
binding neurons project to a different region of the spinal dorsal
horn (inner lamina II) that contains primarily local spinal inter-
neurons. Important questions are whether these two types of
nociceptors have different functional responses to painful stimuli
and whether they have distinct roles in specific types of pain.
We use isolated sensory neurons to examine the response
properties of nociceptors to painful stimuli. By using patch-clamp-
recording techniques, we found that IB4-positive nociceptors have
larger magnitude voltage-gated sodium currents. In contrast, IB4-
negative nociceptors had larger noxious heat-induced ion currents,
suggesting that IB4-negative nociceptors are the nociceptors that
respond intensely to noxious heat (11). In addition, IB4-negative
nociceptors are much more responsive to noxious chemicals that
Fig. 1. Painful stimuli such are elevated during inflammation, including low pH and serotonin
as intense heat activate the (C.L.S., unpublished data). One hypothesis, which remains to be
peripheral terminals of noci-
tested, is that IB4-positive nociceptors mediate neuropathic pain,
ceptors. Action potentials are
transmitted along the affer-
whereas IB4-negative nociceptors mediate inflammatory pain (12).
ent axons to the spinal cord. Why Is Morphine Ineffective in Treating Nerve Injury Pain?
The central terminals of IB4-
Opioid analgesics such as morphine are universally regarded as the
negative unmyelinated noci-
ceptors synapse in lamina I
most powerful pain-relieving drugs. Morphine acts through the
and outer lamina II, whereas ␮-opioid receptor to inhibit signals that transmit pain (13). Pain that
IB4-positive unmyelinated no- follows direct injury to a peripheral nerve is called neuropathic pain.
ciceptors terminate in inner Unfortunately, it is still not known what mechanisms underlie this
lamina II. By means of chemi- prevalent pain syndrome. Neuropathic pain is an anomaly because
cal transmission, nociceptors it is insensitive to morphine as well as other opioid drugs and is
activate spinal neurons that currently best managed with antidepressants and antiepileptics (14).
send axons across the spinal Neuropathic pain may be insensitive to morphine because damage
cord and up fiber tracts and
of primary afferent nerves results in decreased expression of
terminate in the medulla,
midbrain, and thalamus. Tha-
␮-opioid receptors on nociceptors and spinal neurons in the pain
lamic neurons project to re- pathway, thus reducing the efficacy of morphine (15). In addition,
gions of the cortex including other substances may modulate the efficacy of morphine. For
the somatosensory cortex. example, when the neuropeptide cholecystokinin (CCK) is applied
to the spinal cord, it reduces the inhibitory effects of morphine (16).
At the cellular level, ␮-receptors and CCK receptors are expressed
in the same spinal neurons, suggesting that CCK may directly inhibit
development of novel pain therapies that target specific mecha-
actions of morphine by means of signaling mechanisms within a
nisms on identified populations of nociceptors. given neuron (17). Furthermore, activation of ␮-receptors increases
Nociceptors can be divided into two general types. A-fiber release of CCK neuropeptide, which then reduces the effectiveness
nociceptors have lightly myelinated axons, conduct action potentials of morphine in a feedback manner (17). Thus, multiple mecha-
rapidly, and have medium- to large-diameter cell bodies. A-fibers nisms, including decreased ␮-receptors and increased CCK-
mediate the fast, pricking quality of pain. C-fibers have unmyeli- induced inhibition of morphine, make opioids ineffective in treating
nated axons, conduct action potentials slowly, and have small- neuropathic pain.
diameter cell bodies. C-fibers mediate the slower, burning quality Understanding the molecular and cellular mechanisms that
of pain. C-fibers comprise around 70% of all nociceptors. Two underlie the initiation of pain and the development and main-
classes of C-fibers have been identified. One class contains a variety tenance of plasticity in primary afferent and spinal neurons will
of neuropeptides, including substance P and calcitonin gene-related undoubtedly reveal novel targets for the discovery of more
peptide, and expresses trkA receptors, the high-affinity receptor for effective, more specific pain therapies.
nerve growth factor (8). These neurons project to the outermost
region of the spinal dorsal horn (lamina I and outer lamina II) and This work was supported by National Institutes of Health Grants
terminate largely on spinal neurons that project to higher-order NS40538-01 (to C.L.S.) and NS36929 (to M.S.G.), and by Nature Science
pain centers in the brain (Fig. 1). The other class contains few Foundation of China Grant 39840160 (to X.Z.).

1. Loeser, J. D., Butler, S. H., Chapman, C. R. & Turk, K. C., eds. (2001) Bonica’s Management 10. Bennett, D. L., Michael, G. J., Ramachandran, N., Munson, J. B., Averill, S., Yan, Q.,
of Pain (Lippincott, Philadelphia). McMahon, S. B. & Priestley, J. V. (1998) J. Neurosci. 18, 3059–3072.
2. Woolf, C. J. & Salter, M. W. (2000) Science 288, 1765–1768. 11. Stucky, C. L. & Lewin, G. R. (1999) J. Neurosci. 19, 6497–6505.
3. Hunt, S. P. & Mantyh, P. W. (2001) Nat. Rev. Neurosci. 2, 83–91. 12. Snider, W. D. & McMahon, S. B. (1998) Neuron 20, 629–632.
4. Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T. A., Levine, J. D. & Julius, D. 13. Matthes, H. W., Maldonado, R., Simonin, F., Valverde, O., Slowe, S., Kitchen, I., Befort, K., Dierich,
(1997) Nature (London) 389, 816–824. A., Le Meur, M., Dolle, P., et al. (1996) Nature (London) 383, 819–823.
5. Caterina, M. J., Rosen, T. A., Tominaga, M., Brake, A. J. & Julius, D. (1999) Nature
14. Watson, C. P. (2000) Clin. J. Pain 16, Suppl., S49–S55.
(London) 398, 441–446.
15. Zhang, X., Bao, L., Shi, T. J., Ju, G., Elde, R. & Hokfelt, T. (1998) Neuroscience 82, 223–240.
6. Caterina, M. J., Leffler, A., Malmberg, A. B., Martin, W. J., Trafton, J., Petersen-Zeitz,
K. R., Koltzenburg, M., Basbaum, A. I. & Julius, D. (2000) Science 288, 306–313. 16. Kellstein, D. E., Price, D. D. & Mayer, D. J. (1991) Brain Res. 540, 302–306.
7. McCleskey, E. W. & Gold, M. S. (1999) Annu. Rev. Physiol. 61, 835–856. 17. Zhang, X., de Araujo, Lucas, G., Elde, R., Wiesenfeld-Hallin, Z. & Hokfelt, T. (2000)
8. Averill, S., McMahon, S. B., Clary, D. O., Reichardt, L. F. & Priestley, J. V. (1995) Eur. Neuroscience 95, 197–207.
J. Neurosci. 7, 1484–1494. 18. Davis, J. B., Gray, J., Gunthorpe, M. J., Hatcher, J. P., Davey, P. T., Overend, P.,
9. Molliver, D. C., Wright, D. E., Leitner, M. L., Parsadanian, A. S., Doster, K., Wen, D., Yan, Harries, M. H., Latcham, J., Clapham, C., Atkinson, K., et al. (2000) Nature (London)405,
Q. & Snider, W. D. (1997) Neuron 19, 849–861. 183–187.

11846 兩 www.pnas.org兾cgi兾doi兾10.1073兾pnas.211373398 Stucky et al.

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