Clinical Research
The Effect of Tooth Bleaching on Substance P Expression
in Human Dental Pulp
Javier Caviedes-Bucheli, DDS, MSc,* Germán Ariza-García, DDS,†
Silvia Restrepo-Méndez, DDS,* Nestor Ríos-Osorio, DDS,* Nelson Lombana, PhD,‡ and
Hugo Roberto Muñoz, DDS, MA§
Abstract
The purpose of this study was to quantify the effect of
tooth bleaching on substance P (SP) expression in healthy
human dental pulp. Forty pulp samples were obtained
from healthy premolars in which extraction was indicated
for orthodontic reasons. Thirty of these premolars were
assigned into three different tooth-bleaching protocols:
group 1 (n ⫽ 10): Opalescence Xtra Boost (Ultradent
Products, South Jordan, UT) (38% H2O2) for 15 minutes;
group 2 (n ⫽ 10): Lase Peroxide (DMC, Brazil) (35% H2O2)
activated with infrared laser diode (Biolux; BioArt, Brazil)
for 3 minutes, and group 3 (n ⫽ 10): Zoom! Whitening
System (Discuss Dental, Culver City, CA) (25% H2O2) light
activated for 20 minutes. The remaining 10 healthy pre-
molars serve as a control group. Teeth were anesthetized
immediately after bleaching and were extracted 10 min-
utes later. All pulp samples were processed and SP was
measured by radioimmunoassay. Greater SP expression
was found in the Zoom! Whitening System, followed by
the Lase Peroxide group, Opalescence Xtra Boost, and the
lower SP values were for the control group. Analysis of
variance showed statistically significant differences be-
tween groups (p ⫽ 0.0001). Tukey HSD post hoc tests
showed significant differences in the light (p ⬍ 0.01) and
laser (p ⬍ 0.05) activated bleaching systems when com-
pared with control values. It can be concluded that light-
and laser-activated tooth-bleaching systems increase SP
expression in human dental pulp significantly higher than
normal values. (J Endod 2008;34:1462–1465)
Key Words
Human dental pulp, neuropeptide, substance P, tooth
bleaching
From the Departments of *Endodontics and †Oral Reha-
bilitation, School of Dentistry, Pontificia Universidad Javeriana,
and the ‡Department of Chemistry, Universidad de los Andes,
Bogotá, Colombia; and §Department of Endodontics, School of
Dentistry, Universidad de San Carlos de Guatemala, Guate-
mala.
Address requests for reprints to Javier Caviedes-Bucheli,
DDS, MSc, School of Dentistry, Pontificia Universidad Javeri-
ana, Cra 7 No. 40-62 Building 26, Bogotá, Colombia. E-mail
address: javiercaviedes@cable.net.co.
0099-2399/$0 - see front matter
Copyright © 2008 American Association of Endodontists.
doi:10.1016/j.joen.2008.09.013
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D ental pulp inflammation is a complex process involving a wide variety of neuronal
and vascular reactions that are key components of the neurogenic inflammation
that could lead to pulp necrosis (1). Neuropeptides are the major protagonists of the
neuronal component and are present on the sensitive afferent neurons from the trigem-
inal ganglia and on sympathetic fibers from the cervical ganglia (2, 3). Substance P (SP)
is, among others, the most important neuropeptide. Its primary function is to induce
vasodilation, increasing pulpal blood flow allowing rapid and large arrival of inflam-
matory cells and mediators release into the inflammatory site (4).
Pulp tissue undergoes several alterations during neurogenic inflammation, includ-
ing hyperalgesia or sensitization of nerve fibers causing a reduction of pain threshold,
increased inflammatory response because of the arrival of vasoactive substances, and
extravasation of fluids and plasmatic proteins to the interstitial tissue, thereby increasing
pulp pressure on the injury site. These alterations could have permanent consequences
in a low compliance environment, such as dental pulp (5).
Contemporary dentistry is strongly influenced by esthetics, where tooth bleaching
has become a usually requested and/or offered clinical procedure although some
harmful effects over oral tissues, including dental pulp, have been associated with this
treatment (6, 7). Chemicals commonly used for tooth bleaching usually contain some
form of hydrogen peroxide (H2O2) at different concentrations. H2O2 is an oxidant agent
that, with the aid of some chemical or physical activators (ie, enzymes, light or heat),
dissociates in perhydroxyl (HO2⫺) and oxygen (O⫺) radicals. These free radicals,
known as reactive oxygen species, have low molecular weight and are able to denatu-
ralize proteins, penetrate enamel, and diffuse through the organic matrix of dentin to
exert its bleaching effect (8, 9).
Most of the current in-office tooth-bleaching systems use light and/or heat as the
activator source to enhance bleaching efficacy by accelerating the oxygen dissociation
rate, thus reducing the time needed to whiten teeth. It has been shown that by each 10°C
increase in temperature the rate of chemical reactions within the bleaching agent
duplicates, generating greater dissociation and release of free radicals, which will react
more rapidly with pigmented molecules of the tooth (10-12). However, it also has been
reported that a 5°C increase in pulp temperature could have irreversible consequences
to dental pulp (13). Different light-energy sources have been used to activate bleaching
agents, including halogen-curing lights, ultraviolet (UV) and infrared lamps, and lasers
(CO2, argon, and more recently laser diode) (14).
During bleaching, a reduction/oxidation reaction occurs also known as redox
reaction. The oxidant agent, H2O2, dissociates into free radicals with unpaired electrons
and gets reduced by giving these electrons, and, consequently, the substances being
bleached get oxidized by accepting the electrons. This results in a molecular rupture
and in a change in the energy absorption at the molecular level within the pigmented
dental organic matrix, forming simpler and smaller molecules that reflect light in a
different way, creating a successful bleaching effect (15, 16). However, free radicals
released during bleaching are highly reactive and have been associated with several
physiologic and pathological events, including proteins, lipids, and nucleic acids deg-
radation, leading to tissue aging and other degenerative processes (9, 15). The pres-
ence of dentinal tubules within the tooth architecture could allow these free radicals to
reach the pulp tissue and generate these adverse effects (13, 17).
JOE — Volume 34, Number 12, December 2008

It has been shown that, in cultured fibroblasts, H2O2 is toxic to
cells even in lower concentrations like 10 ␮mol/L (0.34 mg/L), inhib-
iting cell proliferation by DNA chain breakage (18). The diffusion of
different H2O2 concentrations through dentin has also been evaluated,
showing that only 15 minutes are needed for H2O2 to diffuse through a
0.5-mm width of dentin, reaching concentrations capable of generating
biological damage in fibroblasts cultures (19).
Tooth-bleaching procedures often generate some type of clinical
symptoms, from dentin hypersensitivity to reversible or irreversible in-
flammatory processes, in which SP could play an important role in the
development of these conditions (20). Up to date, tooth-bleaching ef-
fects on pulp tissue have been studied by histological methods; however,
little is known about neuropeptide release after this procedure. This
knowledge could be useful for assessing SP behavior when routine
clinical procedures are performed and, consequently, contribute to
clinician’s decision making in order to minimize pulp tissue injury.
Therefore, the purpose of this study was to determine the effect of
different tooth-bleaching protocols on SP expression in healthy human
dental pulp.
Materials and Methods
A descriptive comparative study was performed according to Co-
lombian Ministry of Health recommendations regarding ethical issues
in research involving human tissue. Written informed consent was ob-
tained from each patient participating in the study. Forty pulp samples
were obtained from healthy, nonsmoking human donors (18-27 years
old) in whom healthy premolar extractions had been indicated for
orthodontic purposes. All teeth used in this study were caries and res-
toration free with complete root development determined both visually
and radiographically and without signs of periodontal disease.
Teeth were divided into four groups containing five upper and five
lower premolars each: (1) control group: 10 healthy pulps in which
normal SP values were measured, (2) experimental group 1: 10 healthy
premolars in which a 15-minute 38% H2O2 (Opalescence Xtra Boost;
Ultradent Products, South Jordan, UT) bleaching procedure was per-
formed, (3) experimental group 2: 10 healthy premolars in which a
35% H2O2 (Lase Peroxide, DMC, São Paulo, Brazil) activated with an
infrared laser diode (Biolux, BioArt, São Paulo, Brazil) bleaching pro-
cedure was performed for 3 minutes, and (4) experimental group 3: 10
healthy premolars in which a 20-minute light-activated 25% H2O2
(Zoom! Whitening System; Discuss Dental, Culver City, CA) bleaching
procedure was performed. All tooth-whitening systems were used fol-
lowing manufacturer’s instructions.
Sample Collection
Teeth were anesthetized immediately after bleaching by 1.8 mL of
4% prilocaine without vasoconstrictor infiltration injection for upper
premolars and by inferior alveolar nerve block injection for lower pre-
molars. Ten minutes later, they were extracted by conventional meth-
TABLE 1. Pulpal SP Expression after Different Tooth-bleaching Protocols in Healthy Human Premolars
N Mean*
Control group† (normal SP values) 10
Experimental group 1† (Opalescence Xtra Boost) 10
Experimental group 2‡ (Lase Peroxide and Biolux) 10
Experimental group 3 (Zoom! Whitening System) 10
SP, Substance P.
NOTE. ANOVA test showed statistically significant differences between groups (p ⬍ 0.0001).
*Values are presented as SP concentration in picomolars per milligrams of dental pulp tissue.
†Tukey HSD post hoc test showed statistically significant differences with experimental group 2 (p ⬍ 0.05) and 3 (p ⬍ 0.01).
‡Tukey HSD post hoc test also showed a statistically significant difference with experimental group 3 (p ⬍ 0.01).
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Clinical Research
ods. For the control group, extraction was also performed 10 minutes
after anesthetic application.
All teeth were washed with 5.25% sodium hypochlorite after ex-
traction to eliminate remnants of periodontal ligament that could con-
taminate the pulp sample. The teeth were then sectioned using a Zekrya
bur (Dentsply, Tulsa, OK) in a high-speed hand piece irrigated with
saline solution. Pulp tissue was obtained by using a sterile endodontic
excavator, placed on an Eppendorf tube, snap frozen in liquid nitrogen,
and kept at ⫺70°C until use.
Radioimmunoassay
Pulp tissue samples were defrosted without thermal shock, dried
on a filter, and weighed on an analytic balance. Neuropeptides were
extracted by adding 150 ␮L of 0.5 mol/L acetic acid and double boiled
in a thermostat bath for 30 minutes.
SP expression was determined by competition binding assays us-
ing a human SP radioimmunoassay kit from Phoenix Peptide Pharma-
ceutical (Ref. RK-061-05, Belmont, CA). The lowest detection limit of
this kit is 55 pmol SP/mL. Fifty microliters of each sample solution were
incubated in polypropylene tubes at room temperature for 20 hours
with 100 ␮L of primary antibody (1:100 rabbit anti-SP serum solution)
and 100 ␮L of different SP concentrations (10 pg/mL-1,280 pg/mL).
Then, 50 ␮L of 125I-SP were added and left to incubate for another 24
hours.
Bound fractions were precipitated by the addition of 100 ␮L of a
secondary antibody (goat antirabbit immunoglobulin G serum), 100 ␮L
of normal rabbit serum, and 500 ␮L of radioimmunoassay buffer con-
taining 1% polyethylenglycol 4000. After 2 hours of incubation at room
temperature, tubes were spun at 3,000 rpm for 45 minutes at 4°C. The
supernatants were decanted, and pellet radioactivity was read on a
Gamma Counter (Gamma Assay LS 5500; Beckman, Fullerton, CA).
Standard curves of authentic peptide were made in buffers identical to
the tissue extracts. Finally, Scatchard analysis of the binding data as-
sessed the amount of SP present in every sample.
Statistical Analysis
Values are presented as SP concentration in picomolars per mil-
ligrams of dental pulp tissue. Mean, standard deviation, and maximum/
minimum values are presented for each group. Analysis of variance
(ANOVA) test was performed to establish statistically significant differ-
ences between groups (p ⬍ 0.05). Tukey HSD post hoc comparisons
were also performed.
Results
SP was found to be expressed in all pulp samples (Table 1). High-
est SP levels were observed in experimental group III (Zoom! Whitening
System). The mean expression for this group was 1649.52 ⫾ 341.97
pmol SP/mg pulp tissue followed by experimental group II (Lase Per-
oxide activated with infrared laser diode) with a mean SP expression of
Standard Deviation Minimum Maximum
756.94 62.85 678.16 856.32
760.23 141.71 578.64 1092.83
1,054.66 155.55 793.31 1321.20
1,649.52 341.97 1297.73 2107.92
Tooth-bleaching Effect on SP 1463
Clinical Research
1054.66 ⫾ 155.55 pmol SP/mg pulp tissue. The mean expression for
the experimental group 1 (Opalescence Xtra Boost) was 760.23 ⫾
141.71 pmol SP/mg pulp tissue. The lowest SP levels were observed in
the control group samples (healthy pulps without treatment) with a
mean expression of 756.94 ⫾ 62.85 pmol SP/mg pulp tissue. The
ANOVA test showed statistically significant differences between groups
(p ⫽ 0.0001). Tukey HSD post hoc tests showed significant statistical
differences between the control group and experimental groups 2 (p ⬍
0.05) and 3 (p ⬍ 0.01). The difference between experimental groups
2 and 3 was also statistically significant (p ⬍ 0.01). The difference
between the control group and experimental group 1 was not statisti-
cally significant.
Discussion
Tooth bleaching is one of the most common procedures currently
performed in contemporary dentistry. However, some controversy still
exists on the safety of this procedure, showing numerous articles that
defend bleaching as being innocuous to dental tissues, and, conversely,
there is evidence in the literature that chemicals used for tooth bleaching
have deleterious effects on pulpodentin complex (6, 7, 12, 19, 21–24).
Enamel and dentin permeability allows these low–molecular-
weight radicals to penetrate into dental tissues, becoming a potential
hazard to the pulp (9). However, adverse effects of tooth bleaching have
not been studied from a neurovascular approach, and neuropeptide
release in response to this procedure has not been well elucidated. In a
low compliance environment, this kind of aggression could generate an
inflammatory response and induce pulp cells (including fibroblasts and
mesenchymal undifferentiated cells) to undergo apoptosis, therefore
lowering tissue ability to defend itself from future irritants (13).
Furthermore, H2O2 penetration into the pulp tissue could generate
dentinal sensitivity after treatment (20); current evidence suggests that
tissue exposure to SP may contribute indirectly to the development of
hyperalgesia. The inflammatory process generated after tooth bleaching
usually last for approximately 2 weeks. During this time, proinflamma-
tory cytokine release continues, which, in some cases, could perpetuate
SP release for longer periods of time and therefore cause posttreatment
symptoms in some cases (25, 26).
Basal SP values were obtained from healthy premolars in which
extraction was indicated for orthodontics reasons. Local anesthetic
used in all groups of this study was 4% prilocaine without vasoconstric-
tor to prevent neuropeptide expression becoming attenuated by alpha-
adrenergic agonists (ie, vasoconstrictors) as stated by previous authors
(27, 28). There was a 10-minute delay after bleaching procedure be-
fore proceeding with tooth extraction. Because SP release is immediate,
calcium dependent, and of short-term, this period of time appears to be
sufficient for allowing the neuropeptide to be released from terminal
fibers before being degraded by endogenous peptidases (29). Other
authors (25, 30) have speculated on the possible mechanisms for the
increase of extracellular SP, including (1) increased synthesis of the
neuropeptide in the trigeminal ganglia; (2) increased rate of transport;
(3) increased release; and (4) decreased levels of peptidases, which
would result in decreased degradation of SP. More recent evidence has
shown that messenger RNA transcripts are transported to peripheral
terminals, suggesting that peptide synthesis could occur directly in the
peripheral terminals (31). However, in the present study, it is assumed
that increased SP levels are more related to increased release because
10 minutes would not be enough for the other hypothesis to take place.
It is important to point out that different H2O2 concentrations and
different application times were used in the present study, and these are
variables that could have influenced the results presented because it is
assumed that adverse effects to the pulp are proportional to the con-
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centration of the bleaching agent and the time that the tooth is being
exposed to it (14, 16, 24). However, all the bleaching systems tested
were used strictly following manufacturer’s instructions in order to
better simulate normal clinical conditions.
Interestingly, data from the present study showed that tooth-
bleaching systems using 25% and 35% H2O2 with light/heat (UV light
and infrared laser diode) activation resulted in significantly increased
SP levels when compared with basal levels and 38% H2O2 bleaching
without light/heat activation. These results confirm that light/heat appli-
cation over whitening gels generates an increased reaction of H2O2 with
an accelerated release of free radicals with higher kinetic energy, which
clinically traduces into a faster whitening effect (19). On the other hand,
38% H2O2 tooth bleaching without light and/or heat activation does not
increase significantly the SP expression compared with control levels,
suggesting that this tooth-bleaching protocol has the ability to generate
a whitening effect without increasing basal SP levels. These results could
be explained by the diversity of self-defense mechanisms of the pulpo-
dentin complex against free radicals (32).
The first line of defense is enamel, which acts as a mechanical
barrier against external irritants (33). However, because of the free
radicals’ ability to denaturalize proteins and their low molecular weight,
they easily diffuse through enamel matrix and reach dentin (20). When
reactive oxygen species radicals penetrate dentinal tubules, they have to
overcome different defense mechanisms, including the odontoblast
process, dentinal fluids, and collagen fibers, that act as a biological
barrier by interacting with these molecules because of high reactivity of
radicals (34, 35). Moreover, positive intrapulpal pressure and gel osmotic
pressure could oppose to the diffusion of radicals toward the pulp (32).
In case the free radicals reach the pulp tissue, pulp cells have the
ability to synthesize enzymes, like catalase, glutathione peroxidase, and
superoxide dismutase, which are part of the homeostatic system of the
body and serve as a defense mechanism against peroxides and free
radicals. Additionally, synthesis of hemoxigenase-1 (HO-1) is increased
after cell exposure to oxidative stress. HO-1 is a heat shock protein that
rapidly responds in cases of aggressions that threaten cell homeostasis.
Odontoblasts have shown a strong positive staining for HO-1, which in
part could be responsible for the apparent safety of tooth bleaching,
because odontoblasts are the first cells that become in contact with free
radicals inside the dentinal tubule (7).
However, when the amount of highly reactive radicals (HO⫺ and
O⫺) that penetrate tooth mineralized tissues overcomes these pulpo-
dentin complex initial defense mechanisms, irritation of nerve sensory
fibers occurs with the consequent neuropeptide release, triggering a
more aggressive defense mechanism known as inflammation (1, 5, 10).
This could explain why light-/heat-activated tooth-bleaching systems
generate an increased SP expression in the present study, whereas the
aggression of 38% H2O2 alone could be more tolerable or controlled by
pulp defense mechanisms.
Another possible explanation to the significantly higher SP levels in
the 25% H2O2 activated with UV light compared with the other groups is
the fact that H2O2 interacts intensely with lights of a wavelength smaller
than 300 nm (UV light range), generating a greater ionic dissociation
and an increased free radicals release (12).
The increased levels of SP found in the present study may be
clinically relevant because they could develop a neurogenic inflamma-
tory reaction in pulp tissue, which may not be evidenced with severe or
spontaneous pain because of the degenerative processes that free rad-
icals produce over cells, nerve fibers, and blood vessels. Therefore, it
can be concluded that light- and/or heat-activated tooth-bleaching sys-
tems generate a significant increase in pulpal SP levels. These data
should make clinicians aware that performing this type of tooth-bleach-
ing procedure, even under the best conditions, represents an injury to
JOE — Volume 34, Number 12, December 2008

the pulpodentin complex, which could generate neurogenic and vascu-
lar reactions, including the release of SP.
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Tooth-bleaching Effect on SP 1465