S2 Journal of Pain and Symptom Management Vol. 19 No. 1(Suppl.

) January 2000

Proceedings Supplement
NMDA-Receptor Antagonists: Evolving Role in Analgesia

Update on the Neurophysiology of Pain

Transmission and Modulation: Focus on the
NMDA-Receptor
Gary J. Bennett, PhD
Department of Neurology, MCP Hahnemann University, Philadelphia, Pennsylvania, USA

Abstract
Pain is detected by two different types of peripheral nociceptor neurons, C-fiber nociceptors with
slowly conducting unmyelinated axons, and A-delta nociceptors with thinly myelinated axons.
During inflammation, nociceptors become sensitized, discharge spontaneously, and produce
ongoing pain. Prolonged firing of C-fiber nociceptors causes release of glutamate which acts on
N-methyl-D-aspartate (NMDA) receptors in the spinal cord. Activation of NMDA receptors
causes the spinal cord neuron to become more responsive to all of its inputs, resulting in
central sensitization. NMDA-receptor antagonists, such as dextromethorphan, can suppress
central sensitization in experimental animals. NMDA-receptor activation not only increases
the cell’s response to pain stimuli, it also decreases neuronal sensitivity to opioid receptor
agonists. In addition to preventing central sensitization, co-administration of NMDA-receptor
antagonists with an opioid may prevent tolerance to opioid analgesia. J Pain Symptom
Manage 2000;19:S2–S6. © U.S. Cancer Pain Relief Committee, 2000.

Key Words
NMDA-receptor antagonists, pain transmission, opioid tolerance, central sensitization,
allodynia, hyperalgesia, neuropathy

Introduction injury (neuropathic pain) is due, at least in

For many years, the neurophysiological anal-
ysis of pain transmission focused on responses
evoked by an acute noxious stimulus, e.g., a
pinprick or a few seconds exposure to painful
heat. It was realized that clinically significant
pain might be very different, but the hope was
that it would be different in degree, not in
kind. We now know that this is not true—
chronic pain caused by inflammation or nerve
Address reprint requests to: Gary J. Bennett, PhD, De-
partment of Neurology, MCP Hahnemann Universi-
ty, Broad and Vine Streets, Philadelphia, PA 19102-
1192.
Accepted for publication: September 17, 1999.
part, to unique mechanisms in the peripheral
and central nervous system.1
Peripheral Nervous System
The skin, muscle and tendon, periosteum
and synovium, heart and blood vessels, and the
viscera (or the connective tissues capsules that
encase them) are all innervated by somatosen-
sory primary afferent neurons that are special-
ized to respond to stimuli that cause, or
threaten to cause, tissue injury. These pain-
sensing afferent neurons, called “nocicep-
tors,” come in two general types, one with
slowly conducting unmyelinated axons (C-fiber
nociceptors) and the other with thinly myeli-

© U.S. Cancer Pain Relief Committee, 2000 0885-3924/00/$–see front matter

Published by Elsevier, New York, New York PII S0885-3924(99)00120-7
Vol. 19 No. 1(Suppl.) January 2000 NMDA-Receptors and Pain Transmission S3

nated axons (A-delta nociceptors). In normal
tissue they are silent in the absence of tissue in-
jury; when injury occurs, their rate of discharge
increases as a function of the amount of tissue
damage, i.e., nociceptors signal the occurrence
of pain and encode its intensity.
In the presence of inflammation, nocicep-
tors acquire new characteristics and are said to
be sensitized: (1) They begin to discharge
spontaneously. This spontaneous, or ongoing,
discharge is at least partly responsible for the
ongoing pain (soreness) that follows a tissue
injury. (2) Their threshold for activation is de-
creased such that normally innocuous stimuli
now cause pain (e.g., the pain felt when lightly
touching a burn; a phenomenon called allo-
dynia). (3) Their stimulus–response curves are
shifted to the left, such that a noxious stimulus
causes more pain than normal, a condition
called hyperalgesia (e.g., the pain of being
slapped on a sunburnt back). The decrease in
threshold and the leftward shift of the stimu-
lus–response function underlie the tenderness
of an injured region and its immediate sur-
round. Sensitized nociceptors also acquire an
excitatory response to norepinephrine; thus,
there is a link between pain and sympathetic
nervous system discharge.2,3
In the case of neuropathic pain, nociceptors
also change their characteristics. If their axon
has been interrupted, the regenerating sprout
may discharge spontaneously and become ex-
tremely sensitive to mechanical, thermal, and
ionic stimulation. Similar, but less pronounced,
changes are seen in nociceptors that escape in-
jury themselves but travel in the vicinity of
damaged axons.4–6
Central Nervous System
Spontaneously discharging nociceptors will
give rise to ongoing pain. Unfortunately, that is
not all. Unmyelinated (C-fiber) nociceptors re-
lease glutamate as their neurotransmitter. The
spinal cord neurons that receive input from
C-nociceptors express three subtypes of gluta-
minergic receptor: the N-methyl-D-aspartate
(NMDA) subtype, the kainate/AMPA (l-amino-
3-hydroxy-5-methylsoxasole-propionic acid) sub-
type, and the metabotropic subtype. Glutamate
released from C-nociceptors and acting at
NMDA receptors evokes a change in the sensi-
tivity of the postsynaptic cell such that it re-
sponds more strongly to all of its inputs (Fig-
ure 1), an effect called central sensitization.
Very recent data suggest that something simi-

Fig. 1. An experiment showing the effects of NMDA-receptor antagonists on central sensitization. Following de-
cerebration and spinalization under general anesthesia, rats were prepared for the electrophysiological recording
of the discharges of flexor motoneurons innervating the thigh. Flexor motoneuron discharges were evoked by a
standardized painful pinch to the toes every 5 minutes. The motoneuron discharge causes the pain withdrawal re-
flex; in humans, the magnitude of the reflex corresponds to the magnitude of pain perceived. Prior to painting
the skin with mustard oil (MO), each pinch evokes a fairly constant baseline pain withdrawal reflex. Mustard oil, a
vesicant that selectively excites C-nociceptors, causes an intense burning pain sensation of about 1 minute dura-
tion. Following the pain input caused by MO, the reflex is greatly enlarged for over an hour. The increased reflex,
and the increased perceived pain that would accompany it, indicate the presence of central sensitization. Pretreat-
ment (left-hand graph) with NMDA antagonists (CPP or MK-801) prevents central sensitization, whereas post-
treatment (right-hand graph) reverses it. Reproduced with permission from Woolf and Thompson.7
S4
lar may also be happening via glutamate activa-
tion of kainate/AMPA channels, but most of the
data in hand implicates the NMDA receptor.
Activation of the NMDA receptor causes the
spinal cord neuron to become more respon-
sive to all of its inputs, including input from
damaged or sensitized nociceptors and input
from low-threshold mechanoreceptors (“touch”
fibers). It is important to note that central sen-
sitization is evoked by any kind of C-nociceptor
input.8 Normal input from uninjured tissue
produces a small and fleeting amount of cen-
tral sensitization, but the large and prolonged
input from C-nociceptors that are sensitized as
a consequence of tissue inflammation, or that
discharge spontaneously because of nerve in-
jury, can produce prominent and long-lasting
central sensitization.
Central sensitization has been demonstrated
in animals, even in the presence of a surgical
level of general anesthetic. It can be demon-
strated also in the normal human volunteer.
For example, an intradermal injection of cap-
saicin (the active ingredient in chili peppers
and a specific stimulant for C-nociceptors) pro-
duces a very strong burning pain sensation that
lasts for about 20 minutes. After the injection
pain has waned (and even before that), the
skin surrounding the injection site becomes al-
lodynic and hyperalgesic for hours (Figure 2).
The allodynia and hyperalgesia can be re-
versed by NMDA-receptor blockade.10–12
NMDA-Receptor Antagonists
There is universal agreement that NMDA-
receptor antagonists of diverse chemistry sup-
press central sensitization in experimental
animals (Table 1), and there are several demon-
strations of efficacy in humans.23–27 NMDA-recep-
tor blockers that have been shown to be effec-
tive include some familiar drugs that happen
to have NMDA antagonist properties, e.g., dex-
tromethorphan, dextrorphan, memantine, ket-
amine, and amantadine. The clinical useful-
ness of some of these drugs is limited by a very
narrow therapeutic index due to unacceptable
effects on mental functioning. Ketamine, for
example, has demonstrable efficacy as an NMDA-
receptor antagonist, but its psychotomimetic
effects will probably preclude its use in the
clinic. On the other hand, dextromethorphan
Bennett Vol. 19 No. 1(Suppl.) January 2000
is an antitussive that has been on the market
for many years and has established an excellent
safety record. Memantine also has been shown
in European studies to be well-tolerated in eld-
erly patients to retard the progression of Alzhei-
mer’s disease.
Clinical experience indicates that neuro-
pathic pain is relatively (in some cases almost
completely) resistant to opiate analgesics. Data
from experiments on diverse topics show that
this is due to an interaction between the intra-
cellular events that mediate central sensitiza-
tion and those that regulate the sensitivity of
the mu subtype of opiate receptor. Pain-evoked
NMDA-receptor activation increases the cell’s
responses to its stimuli, while it also decreases
the efficacy of mu-receptor agonists. Thus, a
patient with neuropathic hyperalgesia has a
sort of pain-evoked opiate tolerance, even in
Fig. 2. Central sensitization demonstrated in a nor-
mal human volunteer. An intradermal injection of
100 mg of capsaicin (in a volume of 10 ml) is made
on the volar forearm. Ten to 20 minutes of intense
burning pain follows the injection. Thereafter the
skin surrounding the injection site is allodynic and
hyperalgesic. Stroking the skin with a cotton swab
evokes a burning pain sensation. Poking (not pene-
trating) the skin with a pin (punctate) evokes a
strong, stinging, electric shock-like pain that far ex-
ceeds the normal, barely painful sensation evoked
by pin prick. The injection raises a bleb that be-
comes analgesic (C-nociceptors fall silent and are
not excitable after discharging strongly to the capsa-
icin). A small region surrounding the bleb becomes
hypersensitive to heat stimuli. A prominent flare re-
sponse is evoked in an area surrounding the bleb.
Note that the allodynic and hyperalgesic response to
stroking and punctate stimuli must be mediated via
a change in CNS processing because the capsaicin
does not diffuse from the injection site. Reproduced
with permission from LaMotte et al.9
Vol. 19 No. 1(Suppl.) January 2000 NMDA-Receptors and Pain Transmission S5

Table 1
Effects of Diverse NMDA-Receptor Blockers on Neuropathic Pain Seen in Experimental
Models of Painful Peripheral Neuropathy in the Rat
Drug Model Route Test Ref.

MK-801 CCI13 i.p. heat Davar et al.14

CCI i.t. heat Yamamoto and Yaksh15
CCI i.t. heat, spon Mao et al.16
K & C17 i.t. M-allo Chaplan et al.18
AP-5 CCI i.t. Heat Yamamoto and Yaksh15
K&C i.t. M-allo Chaplan et al.
Ketamine CCI i.t. Heat Yamamoto and Yaksh15
CCI i.t. heat, spon Mao et al.16
Dextromethorphan, dextrorphan CCI i.p., i.t. heat Tal and Bennett19
CCI i.t. heat Mao et al.20
K&C i.t. M-allo Chaplan et al.18
Memantine CCI i.p. heat Eisenberg et al.21
CCI i.p. heat Chaplan et al.18
Mg 11 CCI i.t. heat Xiao and Bennett22
CCI 5 the chronic constriction model of Bennett and Xie13; K&C 5 the spinal nerve ligation model of Kim and
Chung17; i.p. 5 intraperitoneal dosing; i.t. 5 intrathecal dosing (onto the surface of the lumbar spinal cord); heat 5
heat-hyperalgesia; spon 5 spontaneous pain behaviors; M-allo 5 mechano-allodynia.

the absence of opiate treatment. Conversely,
opiate tolerance appears to engage intracellu-
lar events similar to those engaged by pain-
evoked NMDA-receptor activation. Thus, the
opiate-tolerant patient has a central sensitiza-
tion–like hyperalgesia.
Conclusion
The resistance of certain kinds of pain to
opiate analgesia, or tolerance, was generally
thought to involve simple receptor downregu-
lation. We now know that the mechanisms of
tolerance interact directly with pain sensitivity.
Understanding these mechanisms, which in-
clude glutamate-mediated activation of NMDA
receptors, points to the possibility of improving
opiate analgesic therapy with the co-adminis-
tration of an NMDA-receptor antagonist.
References
1. Bennett GJ. Neuropathic pain. In: Wall PD,
Melzack R, eds. Textbook of pain, 3rd ed. Edin-
burgh, London: Churchill Livingstone, 1994:201–224.
2. Meyer RA, Campbell JN, Raja SN. Peripheral
neural mechanisms of nociception. In: Wall PD,
Melzack R, eds. Textbook of pain, 3rd ed. Edin-
burgh, London: Churchill Livingstone, 1994:201–224.
3. Sato J, Suzuki S, Iseki T, et al. Adrenergic excita-
tion of cutaneous nociceptors in chronically in-
flamed rats. Neurosci Lett 1993;164:225–228.
4. Kajander KC, Bennett GJ. The onset of a painful
peripheral neuropathy in rat: a partial and differen-
tial deafferentation and spontaneous discharge in
A-beta and A-delta primary afferent neurons. J Neu-
rophysiol 1992;68:734–744.
5. Devor M. The pathophysiology of damaged
peripheral nerves. In: Wall PD, Melzack R, eds. Text-
book of pain, 3rd ed. Edinburgh, London: Churchill
Livingstone, 1994:201–224.
6. Perl ER. A reevaluation of mechanisms leading
to sympathetically related pain. In: Fields HL, et al.,
eds. Pharmacological approaches to the treatment
of chronic pain: new concepts and critical issues. Se-
attle, WA: IASP Press, 1994:129–150.
7. Woolf CJ, Thompson SWN. The induction and
maintenance of central sensitization is dependent
on N-methyl-D-aspartic acid receptor activation: im-
plications for the treatment of post-injury pain hy-
persensitivity states. Pain 1991;44:293–299.
8. Gracely RH, Lynch S, Bennett GJ. Painful neu-
ropathy: altered central processing, maintained dy-
namically by peripheral input. Pain 1992;51:175–
194.
9. LaMotte RH, Shain CN, Simone DA, et al. Neu-
rogenic hyperalgesia: psychophysical studies of un-
derlying mechanisms. J Neurophysiol 1991;66:190–
211.
10. Sang CN, Gracely RH, Max, MB, et al. Capsaicin-
evoked mechanical allodynia and hyperalgesia cross
nerve territories: evidence for a central mechanism.
Anesthesiol 1996;85:491–496.
11. Liu M, Max MB, Robinovitz E, et al. The human
capsaicin model of allodynia and hyperalgesia:
sources of variability and methods for reduction. J
Pain Symptom Manage 1998;16:10–20.
12. Sethna N, Liu M, Gracely R, et al. Analgesic and
S6
cognitive effects of intravenous ketamine-alfentanil
combinations vs. either drug alone after intradermal
capsaicin in normal subjects. Anesth Analg 1998;86:
1250–1256.
13. Bennett GJ, Xie Y-K. A peripheral mononeurop-
athy in rat that produces disorders of pain sensation
like those seen in man. Pain 1988;33:87–107.
14. Davar G, Hama A, Deykin A., Vos B, Maciewicz
R. MK-801 blocks the development of thermal hype-
ralgesia in a rat model of experimental painful neu-
ropathy. Brain Res 1991;553:327–330.
15. Yamamoto T, Yaksh TL. Spinal pharmacology of
thermal hyperesthesia induced by constriction in-
jury of sciatic nerve: excitatory amino acid antago-
nists. Pain 1992;49:121–128.
16. Mao J, Price DD, Mayer DJ, Lu J, Hayes RL. In-
trathecal MK 801 and local nerve anesthesia syner-
gistically reduce nociceptive behaviors in rats with
experimental peripheral mononeuropathy. Brain
Res 1992;576:254–262.
17. Kim SH, Chung JM. An experimental model for
peripheral neuropathy produced by segmental spi-
nal nerve ligation in the rat. Pain 1992;50:355–363.
18. Chaplan SR, Malmberg AB, Yaksh, TL. Efficacy
of spinal NMDA-receptor antagonism in formalin
hyperalgesia and nerve injury evoked allodynia in
the rat. Pharmacol Exp Therap 1997;280:829–838.
19. Tal M, Bennett GJ. Neuropathic pain sensations
are differentially sensitive to dextrorphan. NeuroRe-
port 1994;5:1438–1440.
20. Mao J, Price DD, Hayes RL, Lu J, Mayer DJ,
Frenk H. Intrathecal treatment with dextrorphan or
ketamine potently reduces pain-related behaviours
Bennett Vol. 19 No. 1(Suppl.) January 2000
in a rat model of peripheral mononeuropathy.
Brain Res 1993;605:164–168.
21. Eisenberg E, LaCross S, Strassman AM. The
clinically tested N-methyl-D-aspartate receptor antag-
onist memantine blocks and reverses thermal hyper-
algesia in a rat model of painful mononeuropathy.
Neurosci Lett 1995;187:17–20.
22. Xiao W-H, Bennett GJ. Magnesium suppresses
abnormal pain responses via a spinal site of action in
rats with an experimental peripheral neuropathy.
Brain Res 1994;666:168–172.
23. Eide PK, Jorum E, Stubhaug A, et al. Relief of
post-herpetic neuralgia with the N-methyl-D-aspartic
acid receptor antagonist ketamine: a double-blind,
cross-over comparison with morphine and placebo.
Pain 1994;58:347–354.
24. Max MB, Byas-Smith MG, Gracely RH, et al. In-
travenous infusion of the NMDA antagonists, ket-
amine, in chronic post-traumatic pain and allodynia: a
double-blind comparison with alfentanil and placebo.
Clin Neuropharmacol 1995;18:360–368.
25. Persson J, Axelsson G, Hallin RG, et al. Benefi-
cial effects of ketamine in a chronic pain state with
allodynia, possibly due to central sensitization. Pain
1995;60:217–222.
26. Nelson KA, Park KM, Robinovitz E, et al. High-
dose oral dextromethorphan versus placebo in pain-
ful diabetic neuropathy and postherpetic neuralgia.
Neurol 1997;48:1212–1218.
27. Eisenberg E, Pud D. Can patients with chronic
neuropathic pain be cured by acute administration
of the NMDA-receptor antagonist amantadine? Pain
1994;74:37–39.