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Pain Medicine 2013; 14: 13811387
Wiley Periodicals, Inc.
TRANSLATIONAL RESEARCH SECTION
Original Research Article
Mechanisms of Topical Analgesics in
Relieving Pain in an Animal Model of
Muscular Inflammation
Wan-Ru Duan, MD,* Jie Lu, BS,* and
Yi-Kuan Xie, BS*
*Institute of Basic Medical Sciences, Chinese
Academy of Medical Sciences, School of Basic
Medicine, Peking Union Medical College, Beijing;
Department of Neurosurgery, Xuan Wu Hospital
affiliated to Capital Medical University, Beijing, China
Reprint requests to: Yi-Kuan Xie, BS, Department of
Anatomy, Histology and Embryology, Institute of Basic
Medical Sciences, Chinese Academy of Medical
Sciences, School of Basic Medicine, Peking Union
Medical College, no. 5 Dongdansantiao, Beijing
100005, China. Tel: +86 10 69156469; Fax: +86 10
65196460; E-mail: xieyk1938@yahoo.com.cn.
Abstract
Objective. To investigate the possible mechanisms
of topical analgesics in relieving pain in an animal
model of muscular inflammation.
Methods. Adult Sprague-Dawley rats of both sexes
were injected with complete Freunds adjuvant to
induce inflammation in the anterior tibialis muscle of
left hindlimb. One of two types of topical analgesics:
Xiaotong Tiegao (XTT), a Tibetan herb compound, or
Capzasin (CAP), a cream containing 0.1% capsaicin,
was applied to the skin over the inflamed anterior
tibialis muscle. The following experiments were per-
formed: pain behavioral tests, evaluation of plasma
extravasation in the affected limb, and electrophysi-
ological recordings of afferent nerve fibers.
Results. The behavioral experiments demonstrated
that applications of either type of topical analgesic
to the skin over the inflamed muscle significantly
reduced muscular inflammatory pain, as indicated
by the increased weight bearing capacity on the
affected hindlimb (with latencies of 10 minutes for
XTT and 12 hours for CAP). Meanwhile, both anal-
gesics caused plasma extravasation in the affected
skin. Electrophysiological recordings from the affer-
ent fibers in the related cutaneous nerve indicated
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that topical analgesics selectively activated
C-fibers, but not A-fibers innervating the same
region of receptive field. The latency and duration of
C-fiber activation was similar to those of the reduc-
tion of muscular inflammatory pain. On the contrary,
topical analgesics substantially decreased C-fiber
afferent spontaneous firing in the nerve innervating
the inflamed muscle. Moreover, denervation of the
affected skin blocked the analgesic effects of both
topical analgesics in muscular inflammatory pain.
Conclusion. This study suggests that topical anal-
gesics may reduce the nociceptive input from
inflamed muscles via a reflex mechanism by activat-
ing the cutaneous nociceptive afferents.
Key Words. Topical Analgesics; Muscular Inflam-
matory Pain; C-Fiber Activation; Skin Plasma
Extravasation
Introduction
Topical analgesics have been widely applied to relieve pain
since ancient times in China and worldwide. Chinese tra-
ditional medicine such as plasters (Gao-Yao) are a
popular treatment for patients suffering from inflammatory
pain in the deep tissue, including injury to the joint liga-
ment, soft tissue contusion, or muscle sprain. In western
medicine, pastes or plasters containing capsaicin have
also been clinically been proved effective in the treatment
of muscular or joint pain [1,2]. Although a number of
reports have been published to confirm the efficacy of
pain-relieving topical plasters [3], there were few study
regarding the mechanisms of topical analgesics. In addi-
tion, most of the published studies were focused on the
ability of drugs in transcutaneous penetration, transdermal
absorption, or binding to the cutaneous nociceptive
receptors after being applied to the skin [1]. However,
transdermal absorption studies have already indicated
that the majority of topically applied drugs, regardless the
ingredients tested, stay in the epidermis without reaching
the dermis layer [4]. Only a minimal concentration of
drugs, if any, can penetrate the epidermis and reach the
deep tissue. These results, obviously contradictory to the
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Duan et al.
proved efficacy of topical analgesics, disprove the hypoth-
esis that these drugs act directly on deep tissue targets.
This study will explore the possible mechanisms of topical
analgesics using behavioral and neurophysiological tech-
niques. We propose that topical analgesics relieve pain in
the deep tissue by activating cutaneous C-fibers.
Materials and Methods
Establishment and Behavioral Evaluation of an Animal
Model of Muscular Inflammatory Pain
A total of 20 male and 20 female adult Sprague-Dawley
rats aged 78 weeks were used in this study. The experi-
mental procedures were approved by the Animal Use and
Care Advisory Committee of the Institute of Basic Medical
Sciences, Chinese Academy of Medical Sciences. To
induce muscular inflammation, 100 L of complete
Freunds adjuvant (CFA, #F5881, Sigma, St. Louis, MO,
USA; composed of inactivated and dried mycobacteria)
was injected into the left anterior tibialis muscle of animals
under clear consciousness, and 100 L of sterile saline
was injected into the right side as a control.
To evaluate the intensity of inflammatory pain, we mea-
sured the differences in weight bearing capacity between
the left (experimental) and right (control) hindlimbs on the
3rd day after injection using an incapacitance tester (pur-
chased from the Institute of Biomedical Engineering,
Chinese Academy of Medical Sciences and Peking Union
Medical Sciences) [5,6]. Briefly, rats were placed in an
angled clear plastic chamber with each hind paw resting
on a separate force plate. The weight bearing capacity (g)
of each hind limb was automatically averaged over a
10-second period. Each data point was demonstrated as
the difference score (g) over the left (experimental) minus
right (control) hindlimb and averaged for three repetitions.
The difference scores for weight bearing between the two
hindlimbs in nave rates were close to zero (data not
shown). A significant decrease in the difference score (i.e.,
more negative) after CFA injection indicated that the
animal model of chronic muscle inflammatory pain was
successfully established.
Evaluation of the Effect of Topical Analgesics
To infer the analgesic effects, topical analgesics were
applied to the skin over the inflamed tibialis anterior
muscle. We chose two types of widely used topical anal-
gesics with clinically approved code numbers by Chinese
State Food and Drug Administration (SFDA) or US Food
and Drug Administration: One is a famous topical analge-
sic in traditional Chinese medicine, Xiaotong Tiegao (XTT,
brown traditional medical power and wetting agent adher-
ing to the inside of patches, manufactured by QiZheng
Zangyao, Tibet Cheezheng Tibetan Medicine Co., Beijing,
China; SFDA Code No. Z54020113) [7,8]; Another is
Capzasin (CAP), a popular topical analgesic in the United
States (cream contain 0.1% capsaicin, manufactured by
Chattam, Chattanooga, TN, USA; NDC product code no.
41167-7518) [9,10].
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After depilation on both hindlimbs, a sticky patch contain-
ing the drug power or cream was applied to the anterior
tibial skin of the experimental side, and recorded the
changes in weight; distribution and difference score were
recorded at different time points: 20, 10, 0, 10, 20, 30,
40, 50, and 60 minutes. The value of each time point was
averaged of three repeated measurements. Preliminary
experiments using the same type of patch containing no
drugs on the skin showed no effects on the difference
score in nave or CFA-injected rats (data not shown).
An additional denervation experiment was performed to
find out whether the drugs take effect by physical pen-
etration or by activating nerve terminals in the skin. In a
subgroup of animals (N = 14), the anterior tibial skin was
denervated by excising the lateral cutaneous branches of
the superficial peroneal nerve. After the surgery, the ante-
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rior tibial skin failed to respond to nociceptive mechanical
stimuli (such as a pinch by tweezers), indicating a suc-
cessful denervation. CFA injection was then performed 3
days after the denervation surgery, followed by the behav-
ioral tests described above.
Orthodromic Recordings of Afferent
Nerve Microfilaments
In order to study whether drugs applied topically can
influence activities in the cutaneous or muscular afferents,
we recorded the action potential firings from afferent nerve
fibers innervating the skin of the target area and the ante-
rior tibial muscle as described previously [11,12]. Briefly,
57 days after CFA injection, the rats were anesthetized
with pentobarbital sodium (50 mg/kg, i.p.). The common
sciatic nerve was exposed at the middle of the thigh,
covered by a pool of mineral oil, and kept at 35 1C.
Single afferent fibers were recorded extracellularly from the
desheathed sciatic nerve 20 mm proximal to the CFA-
injected site using silver wire electrodes, a custom-made
low-noise differential amplifier, 100-Hz high-pass and
1-kHz low-pass filters, and an analog-digital interface with
software running on a personal computer (Biological
Functional System, BL-420B, made by Chengdu
Taimeng, Sichuan, China) for online analysis. Single elec-
trical pulses were delivered via a pair of bipolar silver
stimulating electrodes placed around the nerve distal to
the recording site to measure the conduction velocity (CV)
of the recorded fiber. According to the CV and the
response to the light touch of skin, the recorded neurons
were classified into C-fiber (CV < 1.5 m/s) or A-fiber
(CV 1.5 m/s).
Qualitative Measurements of Evans Blue Extravasation
Plasma extravasation of Evans Blue dye has been vali-
dated as a method to measure local inflammatory
responses to nociceptive transmitters released from
C-fiber nociceptors [1315]. Briefly, rats were anesthe-
tized with sodium pentobarbital (50 mg/kg, i.p.), injected
with Evans Blue (Sigma, i.v. 0.5%, 5 ml/kg b.w. in saline)
and perfused transcardially with 0.1 M phosphate-
buffered saline (pH 7.4) 20 minutes later. The limbs were

Figure 1 Complete Freunds adjuvant (CFA)-
induced inflammatory pain in muscle was inhibited
by indometacin. *P < 0.05, compared with vehicle.
The vertical axis in the histogram indicates the dif-
ference score (g) between the weight bearing of two
hindlimbs measured from the experimental (left) side
vs the control (right) side. The black square over the
zero line on the vertical axis indicates the range of
2 standard error of the mean(SEM) of the differ-
ence score between the two hindlimbs in the nave
animals. *P< 0.05, compared with averages before
treatment.
photographed, and the difference in the extent of plasma
extravasations of Evans blue was compared between
limbs with applied vs nonapplied topical analgesics.
Data Analysis and Statistics
Behavioral data were compared using nonparametric
repeated measures analysis of variance with Bonferroni
Figure 2 Reduction of inflammatory pain following Xiaotong Tiegao (XTT) (A) or Capzasin (CAP) (B) appli-
cation. *P< 0.05, compared with averages before treatment. Other legends are the same as Figure 1.
Mechanisms of Topical Analgesics Relieving Pain
posttest. Students t-test was used to compare data in all
other experiments. A value of P < 0.05 was considered
significant. N refers to the number of animals used or
fibers sampled in a given group. Data were expressed as
means standard error of the mean.
Results
Injection of CFA into the Muscle Elicited a Reliable
Inflammatory Pain
Starting from the 3rd day after CFA injection, the weight
bearing capacity of the inflammatory hindlimb declined,
and the difference score decreased significantly. An anti-
inflammatory medicine, indometacin (12 mg/kg, p.o.),
produced a significant increase in the different score as
demonstrated in Figure 1 (N = 6, P < 0.05), indicating that
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the inflammatory pain model was successfully established
via a CFA injection of the muscle.
Effects of Topical Analgesia on Inflammatory
Muscular Pain
Both types of topical analgesics applied on the skin over
the left (experiment side) anterior tibialis muscle of the
modeled animals were able to induce a significant
increase in the difference score after a latency ranging
from 8 to 20 minutes for XTT and 12 hours for CAP
(Figure 2), indicating the effectiveness in relieving inflam-
matory pain. After XTT application, the pain relief effects
peaked at around 3050 minutes followed by a wave-like
degrading pattern that lasted for 46 hours (Figure 2A).
CAP application induced similar results as XTT, but with a
longer latency of up to 2 hours (Figure 2B).
Cutaneous Innervation is the Decisive Factor in the
Topical Analgesic Effect
In the last experiment, we confirmed that both XTT and
CAP have similar pain relieving effects. However, there has
been no experimental evidence supporting the notion that
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Duan et al.
topical analgesics take effect by penetrating into deep
tissue. Due to the strong irritation effects of most topical
analgesics such as XTT and CAP, we hypothesize that
these drugs act by stimulating the cutaneous nociceptive
nerve terminals. Based on this hypothesis, the effects of
topical analgesics would be diminished after denervation
of the target skin. Therefore, we designed a subset of
experiments in which the lateral cutaneous branches of
the superficial peroneal nerve innervating the anterior tibial
skin were transected 3 days before the CFA injection. As
demonstrated in Figure 3, application of CAP (N = 6,
Figure 3A) or XTT (N = 8, Figure 3B) on the denervated
skin could no longer relieve the inflammatory pain, as
indicated by the lack of changes in the difference score.
These experiments strongly suggest that topical analge-
sics take effect by acting on cutaneous nerve terminals
rather than penetrating directly to the muscle.
Topical Analgesics Selectively Activate
Cutaneous C-Afferents
Using the Evans blue labeling technique, we were able to
discover the plasma extravasation in the skin over the
inflamed muscle after the application of topical analgesics,
but not in those without drug application (Figure 4A).
These results indicate that the drugs can activate the
cutaneous C-fiber to release inflammatory substances.
Electrophysiological microfilament recordings from the
nerve fibers innervating the skin revealed that neither the
ongoing nor evoked activities of A- fibers were affected
by topical analgesics (Figure 4B), indicating a lack of
effects of these drugs on the A-fiber afferents. However,
application of XTT induced spontaneous discharge from
C-fibers which were silent before the drug application
(e.g., see Figure 4B, N = 16). The shortest latency for XTT
to induce C-fiber discharges is 5 minutes, and the dis-
Figure 3 Capzasin (CAP) (A) or Xiaotong Tiegao (XTT) (B) failed to relieve the muscular inflammatory pain
after the denervation of the skin. Other legends are the same as Figure 1.
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charge frequency is around 58 Hz. Figure 4B represents
a typical recording of C-fiber spontaneous discharges
induced by XTT, while the touch-evoked discharges of
A-fiber remained unchanged.
The possible cooling effects of the solvents which may
evoke activities from cooling- or cold-sensitive C-fibers
could be excluded by the fact that such stimuli usually
have a much shorter latency than the 5 minutes observed
in the drug application in our experiments. The extravasa-
tion of Evans blue observed on the drug-applied skin
region also indicates the activities of nociceptive C-fibers.
Inhibitory Effects of Topical Analgesics on the
Inflammatory Muscular C-Fiber Afferent Activities
In the nerve innervating normal muscles, we did not
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observe any spontaneous afferent activities of C-fibers
despite a large amount of A-fiber muscle spindle activities.
However, in the animal models of CFA-induced inflamma-
tory muscular pain which showed pain-related behaviors,
tonic C-fiber spontaneous discharges of about 49 Hz
were recorded from the deep peroneal nerve innervating
the anterior tibial muscle. In these preparations (N = 10),
XTT was applied to the skin in the background of C-fibers
tonic afferent discharges. After a latency of about 2040
minutes, the spontaneous discharges of C-fibers gradu-
ally decreased, then almost stopped or remained sporadic
(Figure 5). This experiment demonstrated the dynamic
process through which topical application of XTT to the
skin inhibited the C-fibers spontaneous afferent activities
coming from the inflamed muscles. Because the skin and
muscle have been separated via the formation of skin pool
containing mineral oil, it would be unlikely that topical
drugs applied to the skin penetrate directly into the
inflamed muscles.
 Mechanisms of Topical Analgesics Relieving Pain

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Figure 4 Topical application of Xiaotong Tiegao (XTT) induced plasma extravasation and C-fiber discharges.
(A) Extravasation of Evans blue observed on the skin region over the inflamed muscle, indicated with dotted
lines, and was corresponding to the shadowed area applied with XTT on the right side (schematic diagram
of the hind limb). (B) XTT selectively elicited discharges of C-fibers but not A-fibers in the superficial peroneal
nerve. No spontaneous firing was recorded before XTT application. The horizontal bars underlying the
recording traces indicate light touch to the skin.

These studies showed that application of the topical anal-
gesics such as XTT or CAP to the skin can reduce the
afferent activities of the C-fibers innervating the muscles.
This inhibitory effect is possibly not due to the results of
direct penetration of drugs to the inflamed muscle, but
rather to the activation of cutaneous nociceptors. At the
same time, the topical analgesics enhanced the C-fiber
afferent activities from the skin and reduced the C-fiber
afferent activities from the muscle. Therefore, we specu-
late that inputs from the cutaneous nociceptive afferents
may be able to inhibit the dorsal root reflexes of C-fiber
afferents from the inflamed muscles, thereby reducing the

Figure 5 Inhibition of Xiaotong Tiegao (XTT) to afferent C-fiber discharges recorded from the deep peroneal
nerve innervating the tibialis anterior muscle after complete Freunds adjuvant (CFA)-induced inflammation.
The inset (at right upper corner) indicates C-fiber conduction velocity (0.54 m/s) of the unit recorded.

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Duan et al.
release of inflammatory factors in the deep tissue as well
as the nociceptive inputs from the damaged tissue.
Discussion
Topical analgesics are traditional drugs of growing inter-
est. They have been widely applied for relieving various
types of pain in the deep tissue, and are considered to
be convenient, effective, with low risk, and low cost [16].
They are easily accessible in drug stores and supermar-
kets as popular over-the-counter painkillers. There are
certain common features of all kinds of topical analge-
sics: they have some irritation effects which may trigger
skin inflammation or even blistering; they are usually
unsuitable for oral use; in most cases, they are only
applied for relieving pain in deep tissue such as chronic
or inflammatory pain in the muscle and joints, and are
rarely used in relieving pain in the skin. Although topical
analgesics have been widely used for thousands of
years, the mechanisms of relieving pain in deeper tissues
are not fully understood yet. Most previous research
works proposed that topical analgesics can pass through
the skin and reach the pain-originating site in deep
tissues, and some manage to promote the efficacy via
facilitating the penetration of topical analgesics through
the skin [17]. In fact, these studies indicate that the con-
centration of the drugs reaching the pain-originating site
is far below the threshold required to silence the
nociceptors. In the present study, we found that once the
skin was denervated, the inflammatory pain in the muscle
was not relieved by the application of XTT or CAP, indi-
cating that the pain relief in muscle tissue provided by
topical analgesics was closely related to the integrity of
the innervation of local skin and was possibly a result of
topical analgesics-evoked inputs of C-fibers. In the
experiment of recording the afferent fibers from the
inflamed muscle, though the skin receiving the topical
analgesics was almost completely separated from the
muscle by liquid paraffin in order to prevent the drugs
from penetrating into the muscle, the topic analgesic
could still effectively reduce the spontaneous C-fiber
afferent firings from the inflammatory muscle. Both of the
above results mentioned above suggested that the anal-
gesic effect was neither due to the direct penetration of
the topical analgesic, nor to any potential effects on the
excitability of A-fibers, but was rather a result of cutane-
ous C-fiber afferent firings induced selectively by topical
analgesics, at least in the cases of XXT and CAP. The
duration of C-fiber-evoked firing is quite consistent with
that of the pain relief which demonstrates the behavior
indicating a possible causality relationship. We speculate
that the afferent inputs from nociceptors of the skin could
inhibit evoked C-fiber afferent from the deep tissue.
The noxious afferent from different parts of the body may
interact in the center nervous system. Le Bars et al. [18]
have successfully demonstrated a diffuse noxious inhibi-
tory control in dorsal horn convergent neurons, i.e.,
noxious afferents from one side or a certain area of
the body can diffusely inhibit the responses of pain-
transmitting neurons in the spinal dorsal horn from the
1386
other side or other areas. Such diffuse inhibition only
occurs in central nervous system (CNS), not in peripheral
nervous system. However, in the present study, we
found that topical analgesics applied on the surface of
skin significantly inhibited the spontaneous afferent
firings of the C-fibers innervating the inflammatory pain
muscle. Such interactions between the noxious afferent
firings of the peripheral nerves are probably involved in
the dorsal root reflex [19]. The afferent signals of C-fiber
from the skin may inhibit the dorsal root reflex in the
nerve fibers supplying the inflamed muscle, therefore
decreasing the antidromic release of inflammatory
factors in the muscle. As a result, the C-fiber afferent
activities from the inflamed muscle are reduced together
with the pain-related behaviors.
Our proposed mechanisms of topical analgesics could
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be used to explain some phenomena in clinical practice.
For instance, some topical analgesics with strong irrita-
tive effects such as skin inflammation or blistering can
produce unexpected relief of pain in the deep tissue,
while mild topical analgesics induce only weak pain relief.
In traditional Chinese medicine, the efficacy of moxibus-
tion (a treatment that involves putting burning moxa on
target acupuncture points to relieve pain) is dependent
on the temperature of the burning moxa, i.e., within the
acceptable temperature range, a higher temperature
produces stronger curative effects. Moreover, the stimu-
lating temperature has to reach above the threshold of
C-fibers activation in order to achieve a satisfactory
effect [20]. In modern western medicine, topical capsa-
icin has been proved effective in the treatment of neu-
ropathic pain, postherpetic pain, and arthritis pain [21].
However, the side effects of this drug, such as a burning
pain on the skin application site, restricted its application
[22]. We speculate that the so-called side effect of skin
irritation, caused by these topical analgesics, may actu-
ally play a key role in the relieving of deep tissue pain.
Acknowledgments
Supported by: National Natural Science Foundation of
China, Grant no. 39830150. We thank Professor Chao Ma
for English editing.
References
1 Benson HA. Transdermal drug delivery: Penetration
enhancement techniques. Curr Drug Deliv 2005;2(1):
2333.
2 Sawynok J. Topical analgesics in neuropathic pain.
Curr Pharm Des 2005;11(23):29953004.
3 Cameron M, Gagnier JJ, Little CV, et al. Evidence of
effectiveness of herbal medicinal products in the
treatment of arthritis. Part 2: Rheumatoid arthritis.
Phytother Res 2009;23(12):164762.
4 Cal K. Skin disposition of menthol after its application
in the presence of drug substances. Biopharm Drug
Dispos 2008;29(8):44954.

5 Thakur M, Rahman W, Hobbs C, Dickenson AH,
Bennett DL. Characterisation of a peripheral neuro-
pathic component of the rat monoiodoacetate model
of osteoarthritis. PLoS ONE 2012;7(3):e33730.
6 Vermeirsch H, Biermans R, Salmon PL, Meert TF.
Evaluation of pain behavior and bone destruction in
two arthritic models in guinea pig and rat. Pharmacol
Biochem Behav 2007;87(3):34959.
7 Wang X, Cao Y, Pang J, et al. Traditional Chinese
herbal patch for short-term management of knee
osteoarthritis: A randomized, double-blind, placebo-
controlled trial. Evid Based Complement Alternat Med
2012;171706.
8 Du Z. The clinical application and adverse reaction
Qizheng Xiaotong Tiegao. Mod J Integr Tradit Chin
West Med 2007;15868.
9 Abrams DI, Jay CA, Shade SB, et al. Cannabis in
painful HIV-associated sensory neuropathy: A ran-
domized placebo-controlled trial. Neurology 2007;
68(7):51521.
10 Jones VM, Moore KA, Peterson DM. Capsaicin 8%
topical patch (Qutenza)A review of the evidence.
J Pain Palliat Care Pharmacother 2011;25(1):32
41.
11 Xie Y, Zhang J, Petersen M, LaMotte RH. Functional
changes in dorsal root ganglion cells after chronic
nerve constriction in the rat. J Neurophysiol 1995;
73(5):181120.
12 Zhu YL, Xie ZL, Wu YW, Duan WR, Xie YK. Early
demyelination of primary A-fibers induces a rapid-
onset of neuropathic pain in rat. Neuroscience
2012;200:18698.
13 Saria A, Lundberg JM. Evans blue fluorescence:
Quantitative and morphological evaluation of vascular
permeability in animal tissues. J Neurosci Methods
1983;8(1):419.
Mechanisms of Topical Analgesics Relieving Pain
14 McMahon SB, Abel C. A model for the study of vis-
ceral pain states: Chronic inflammation of the chronic
decerebrate rat urinary bladder by irritant chemicals.
Pain 1987;28(1):10927.
15 Koltzenburg M, McMahon SB. Plasma extravasation
in the rat urinary bladder following mechanical, elec-
trical and chemical stimuli: Evidence for a new popu-
lation of chemosensitive primary sensory afferents.
Neurosci Lett 1986;72(3):3526.
16 Seino KK, Foreman JH, Greene SA, Goetz TE, Benson
GJ. Effects of topical perineural capsaicin in a revers-
ible model of equine foot lameness. J Vet Intern Med
2003;17(4):5636.
17 El Maghraby GM, Williams AC, Barry BW. Skin delivery
Downloaded from http://painmedicine.oxfordjournals.org/ by guest on August 23, 2016
of oestradiol from deformable and traditional lipo-
somes: Mechanistic studies. J Pharm Pharmacol
1999;51(10):112334.
18 Le Bars D, Dickenson AH, Besson JM. Diffuse noxious
inhibitory controls (DNIC). II. Lack of effect on non-
convergent neurones, supraspinal involvement and
theoretical implications. Pain 1979;6(3):30527.
19 Lin Q, Wu J, Willis WD. Dorsal root reflexes and cuta-
neous neurogenic inflammation after intradermal injec-
tion of capsaicin in rats. J Neurophysiol 1999;
82(5):260211.
20 Wang X, Jiang G, Chen Z, Feng Y. Thermal charac-
teristic analysis of moibustions hyperthermia by the
infrared imaging technology. Infrared Laser Eng
2010;39(3):2236.
21 Hautkappe M, Roizen MF, Toledano A, et al. Review of
the effectiveness of capsaicin for painful cutaneous
disorders and neural dysfunction. Clin J Pain
1998;14(2):97106.
22 Deal CL, Schnitzer TJ, Lipstein E, et al. Treatment of
arthritis with topical capsaicin: A double-blind trial. Clin
Ther 1991;13(3):38395.
1387