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Anesth Analg 2001;93:419-423
© 2001 International Anesthesia Research Society

PAIN MEDICINE

The Effects of Capsaicin Cream on Prostaglandin-Induced Allodynia

Toshiaki Minami, MD, PhD*, Shiho Bakoshi{dagger}, Hiroyuki Nakano, MD, PhD*, Onori Mine, MD*, Tadatoshi Muratani, MD*, Hidemaro Mori, MD, PhD*, and Seiji Ito, MD, PhD{ddagger}

*Department of Anesthesiology, Osaka Medical College, Takatsuki, Japan; {dagger}Research and Development, Maruishi Pharmaceutical Co. Ltd., Osaka, Japan; and {ddagger}Department of Medical Chemistry, Kansai Medical University, Moriguchi, Japan

Address correspondence and reprint requests to Seiji Ito, MD, PhD, Department of Medical Chemistry, Kansai Medical University, 10-15 Fumizono, Moriguchi 570-8506, Japan. Address e-mail to ito{at}takii.kmu.ac.jp


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Although intradermal injection of capsaicin produces acute pain and secondary hyperalgesia, long-term topical application of capsaicin cream has been used as a medication for pain relief in various pain conditions. We previously reported that intrathecal administration of prostaglandin (PG) E2 and PGF2{alpha} into mice induced touch-evoked pain (allodynia) through capsaicin-sensitive and capsaicin-insensitive afferent fibers, respectively. To clarify the mechanism of an analgesic effect by capsaicin cream, here we applied it to the tail and hind paws of mice and investigated its effects on PGE2- and PGF2{alpha}-induced allodynia. Twenty-four-hour pretreatment of mice with 0.025% or 0.05% capsaicin cream markedly alleviated allodynia induced by PGE2, but not by PGF2{alpha}. These results suggest that the topical application of capsaicin cream modulates capsaicin-sensitive afferents and ameliorates allodynia evoked by PGE2 at the spinal level.

IMPLICATIONS: Topical application of capsaicin cream alleviates touch-evoked pain induced by the intrathecal administration of prostaglandin E2. This study may provide a rationale for the use of capsaicin cream as a therapeutic drug for pain relief.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
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Capsaicin is a pungent component of hot chili peppers and has the chemical name trans-8-methyl-N-vanillyl-6-nonenamide (1,2). When it is applied topically to the skin of animals and humans, capsaicin initially lowers the threshold for thermal, chemical, and mechanical nociception by direct activation of vanilloid receptor 1 (3) on free nerve endings of C fibers. Capsaicin is a neurotoxin that, when a large dosage (50 mg/kg) is administered subcutaneously to neonatal animals, destroys a large subpopulation of small-diameter, mainly unmyelinated, primary afferent C fibers and probably thin-myelinated A{delta} fibers (4). Continued application of capsaicin at small doses to adult animals causes a localized desensitization of nociceptive afferents that can last for several days to weeks. This desensitization is the rationale that has led to the use of capsaicin as a therapeutic drug for pain relief. In fact, topical capsaicin has been tried as an analgesic in a variety of neuropathic pain conditions, such as postherpetic neuralgia, painful diabetic neuropathy, osteoarthritis, the postsurgical pain syndrome, and Guillain-Barré syndrome (1,2).

Prostaglandins (PGs) are a group of bioactive lipids working as local mediators in virtually all tissues and include D, E, F, and I types (5). Because aspirinlike drugs suppress inflammatory responses, including pain, by blocking the synthesis of PGs as well as other effects relevant to suppression of inflammation (6–9), it has been widely accepted that PGs are involved in inflammation. Recent evidence indicates that PGs are critical for the processing of pain, not only by sensitizing peripheral terminals of primary afferent nociceptors (6,7), but also by augmenting the processing of pain information at the spinal level (10–12). We previously reported that the intrathecal (IT) administration of PGE2 and PGF2{alpha} into mice induced touch-evoked pain (allodynia); the mice showed squeaking, biting, and scratching behaviors in response to tactile stimuli (13). We demonstrated that the selective elimination of C fibers by neonatal capsaicin treatment resulted in the disappearance of allodynia induced by PGE2, but not that by PGF2{alpha} (14).

Capsaicin cream (15) and lidocaine patch 5% are the only topical drugs approved by the Food and Drug Administration for the treatment of postherpetic neuralgia, patients suffering from which had scarred areas with abnormal sensation of light touch (mechanical allodynia), pain, or thermal change (warm or cold allodynia). However, the complex mechanism by which capsaicin cream causes analgesia remains incompletely understood. In this study, we therefore investigated the effect of capsaicin cream on PGE2- and PGF2{alpha}-induced allodynia.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Male ddY mice were obtained from Japan SLC (Hamamatsu, Japan). The animals were housed under conditions of a 12-h light-dark cycle, a constant temperature of 22°C ± 2°C, and 60% ± 10% humidity. Four-week-old mice weighing 20 ± 2 g were used in this study. The mice were divided into various groups (n = 6 per group for allodynia and n = 10 per group for the tail-flick test). The animals were used only for a single experiment. This study was conducted with the approval of the Animal Experimentation Committee of Kansai Medical University and in accordance with the guidelines of the ethics committee of the International Association for the Study of Pain (16).

Mice had vehicle or 0.025%, 0.05%, or 0.1% capsaicin cream applied once to the anterior and lateral skin of hind paws and tail 24 h before behavioral experiments. Vehicle cream contained 18% polyoxyethylated castor oil, 17% liquid paraffin, 5% white Vaseline, 4% 1-hexadecanol, 0.1% EDTA disodium salt, and 0.75% triethanolamine. Each application was of approximately 30 mg of cream, which was gently rubbed into the skin for about 10 s. Studies of allodynia were performed as described previously (14). Briefly, a 27-gauge stainless-steel needle (0.35-mm outer diameter) attached to a microsyringe was inserted between the L5 and L6 vertebrae. PGE2 (10 ng per mouse) or PGF2{alpha} (1 µg per mouse) dissolved in sterile saline (5 µL) was injected slowly into the subarachnoid space of vehicle- or capsaicin-pretreated mice. After IT injection, each mouse was placed in an individual 13 x 8.5 x 13 cm Plexiglas enclosure with wood chips on the floor and observed. Mechanical allodynia was assessed once every 5 min over a 50-min period by light stroking of the skin of the hind paws and tail of the mice, twice each, with a paintbrush. The allodynic response was ranked as follows: 0, no response; 1, mild squeaking with attempts to move away from the stroking probe; and 2, vigorous squeaking evoked by the stroking probe, biting at the probe, or strong efforts to escape. Thus, the maximum possible cumulative scores for allodynia of six mice were 2 x 6 = 12 in any 5-min period and 2 x 6 x 10 = 120 over the 50-min experimental period. These values were taken as 100%.

The latency to withdrawal of the tail from radiant heat was determined by placing mice on a clear glass plate. Each mouse was placed in a clear Plexiglas cylinder and allowed to acclimate to this environment for 30 min before testing. An infrared heat source (7370 Plantar test; Ugo-Basile, Verese, Italy) was moved beneath a portion of the tail, and the intensity of the heat stimulus was maintained constant and elicited tail movements at a latency of approximately 10 s.

Data for allodynia were analyzed by nonparametric analyses of variance. Statistical significance (P < 0.05) was further examined by the Dunnett’s test for multiple comparison.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
To assess the analgesic effect of capsaicin cream on PG-induced allodynia, we first examined the conditions of topical application of capsaicin cream. When vehicle or capsaicin cream was applied once to the shaved lower back skin of control mice, they showed painlike responses to tactile stimuli 24 h after application with both vehicle and capsaicin cream. We then tested the application of capsaicin cream to the hairless skin: the anterior and lateral skin of hind paws and tail. In agreement with the observation in humans that strong capsaicin solutions cause a burning sensation after each of the first few topical applications, 0.1% capsaicin cream produced symptoms of excitation 10–20 min after application, together with an increase in spontaneous movements. Some mice given 0.1% capsaicin cream showed tremor in their tails. None of the mice given 0.025% capsaicin cream showed signs of distress or strong irritation. A single application of vehicle or capsaicin cream to hind paws and tail did not induce allodynic behaviors to tactile stimuli 24 h after topical application. These pretreated mice did not induce allodynia after IT saline (Fig. 1). When the scores of allodynia obtained for the overall 50 min were cumulated and expressed as a percentage of the maximum possible score, the allodynic scores of vehicle and 0.025%, 0.05%, and 0.1% capsaicin cream were 10.0% ± 2.2%, 6.8% ± 3.3%, 14.2% ± 6.9%, and 15.8% ± 5.2%, respectively. Application of 0.05% capsaicin cream to hind paws and tail three to four times for 1 day or once a day for 1 wk induced allodynic responses to tactile stimuli of the mice. Therefore, we chose the skin of hind paws and tail as application sites and assessed allodynia 24 h after a single application of capsaicin cream.



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  		Figure 1. Concentration dependencies for the induction of allodynia by 24-h pretreatment of capsaicin cream. Vehicle or 0.025%, 0.05%, or 0.1% capsaicin cream was applied once to the skin of hind paws and tail of mice, and allodynic responses were assessed 24 h after topical application. Assessment of allodynia was made after intrathecal saline once every 5 min for 50 min, as described under Methods. The values (mean ± SEM) represent the percentage of the maximum possible cumulative score of six mice evaluated over the 50-min period.

 
Figure 2 shows the time courses of allodynia evoked by IT PGE2 (10 ng per mouse) and PGF2{alpha} (1 µg per mouse). When PGE2 was administered IT to vehicle cream-treated mice, innocuous tactile stimuli applied to the flank of the mice evoked allodynic responses 5 min after IT injection, and the mechanical allodynia was observed over the 50-min experimental period. Twenty-four-hour pretreatment of mice with 0.025% or 0.05% capsaicin cream significantly alleviated the PGE2-induced allodynia (Fig. 2A). When the allodynic scores obtained for the overall 50 min were cumulated and expressed, the allodynia scores of IT PGE2 were 23.4% ± 12.2% and 21.7% ± 11.3% with 0.025% and 0.05% capsaicin cream-treated mice, respectively; they were much lower than those (63.3% ± 13.6%) with vehicle-treated mice (Fig. 3A). However, there was no significant difference in time course and extent (70.8% ± 5.5%) of allodynia evoked by PGE2 in 0.1% capsaicin cream-treated mice from those in vehicle cream-treated mice (Fig. 2A and 3A).



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  		Figure 2. Time courses of the effects of 24-h pretreatment of capsaicin cream on prostaglandin (PG)-induced allodynia. PGE2 (10 ng, A) or PGF2{alpha} (1 µg, B) was injected into the subarachnoid space of mice pretreated with vehicle and capsaicin cream. Assessment of allodynia was made once every 5 min for 50 min as described under Methods. The values (mean ± SEM) represent the percentage of the maximum possible cumulative scores of six mice evaluated every 5 min.

 


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  		Figure 3. Concentration dependencies for the effects of 24-h pretreatment of capsaicin cream on prostaglandin (PG)-induced allodynia. PGE2 (10 ng, A) or PGF2{alpha} (1 µg, B) was injected into the subarachnoid space of vehicle cream- and capsaicin cream-treated mice. Allodynia was assessed and expressed as described in the legend for Figure 1. The asterisk denotes the significance level, as compared with the respective vehicle cream-treated group. *P < 0.05.

 
In vehicle cream-treated mice, PGF2{alpha} produced prominent allodynia in a time course similar to PGE2 (Fig. 2). However, pretreatment of mice with 0.025%–0.1% of capsaicin cream showed no significant effect on the PGF2{alpha}-evoked allodynia (Fig. 2B and 3B).

To examine an alteration in the C-fiber activity, we measured a thermal threshold in the tail-flick test 24 h after a single topical application of capsaicin cream. As shown in Figure 4, vehicle cream-treated mice responded to radiant heat with a latency of 10.2 ± 0.57 s (mean ± SEM, n = 10). There was no difference in the latency between the vehicle cream-treated control and untreated control (10.4 ± 0.54 s) mice. Twenty-four-hour pretreatment of mice with 0.025% and 0.05% capsaicin cream significantly prolonged the latency to 14.5 ± 0.95 s and 13.9 ± 0.95 s. However, pretreatment of mice with 0.1% capsaicin cream shortened the latency to 8.0 ± 0.82 s.



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  		Figure 4. Effect of pretreatment of capsaicin cream on thermal response. Vehicle or 0.025%, 0.05%, or 0.1% capsaicin cream was applied once to the skin of hind paws and tail of mice, and thermal responses were assessed 24 h after topical application. The latency to withdrawal of the tail from radiant heat was measured as described under Methods. The column represents the mean ± SEM of 10 mice. **P < 0.01 versus vehicle cream-treated mice.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Allodynia is a prominent feature of neuropathic pain as well as inflammatory and postoperative pain. Neuropathic pain represents heterogeneous conditions that cannot be explained by a single etiology or by a particular anatomic lesion. We showed that there are two pathways for the induction of allodynia: capsaicin-sensitive C fibers may participate in PGE2-induced allodynia, and capsaicin-insensitive Aß fibers may participate in PGF2{alpha}-induced allodynia (14). Consistent with our previous observations, we demonstrated here that pretreatment of mice with 0.025% or 0.05% capsaicin cream alleviated allodynia induced by IT PGE2 (Fig. 2A and 3A). However, capsaicin cream showed no effect on the PGF2{alpha}-evoked allodynia (Fig. 2B and 3B). Similar to neonatal capsaicin treatment, long-term application of capsaicin at larger doses is believed to cause loss of unmyelinated nerve fibers, deplete substance P of nerves, inhibit axonal transport of substance P, and reduce conduction in C fibers. However, McMahon et al. (17) reported that the long-term topical application of dilute preparations of capsaicin (<0.1%) clinically desensitizes the rat skin to the neurogenic inflammatory agent mustard oil by purely peripheral actions, because it did not cause cell death of dorsal root ganglion cells and decrease production of substance P, calcitonin gene-related peptide. Although topical application of capsaicin exerts its major pharmacologic effects on the peripheral part of the primary afferent C fibers, this study demonstrates that capsaicin cream modifies the induction of allodynia at the central part of the afferent fibers in the spinal cord.

The most adverse effect of capsaicin is the initial burning sensation that it produces (1). A large population of patients cannot tolerate the burning sensation associated with the first few topical applications of capsaicin, even at commercially available concentrations of 0.025% to 0.075%. In the groups of mice given 0.05% and 0.1% capsaicin cream to the shaved lower-back skin, reddish changes of the applied region were found two to three minutes after application. Furthermore, all mice given 0.1% capsaicin cream showed tremor in their tails. However, no changes were observed in the animals applied with 0.025% capsaicin cream, the same as with the vehicle group. Consistent with these behaviors after capsaicin treatment, the thermal latency was reduced by 24 hours of pretreatment with 0.1% capsaicin cream (Fig. 4). Conversely, the thermal latency was prolonged by 0.025% and 0.05% capsaicin cream, suggesting that the 24-hour pretreatment of capsaicin cream may deplete neurotransmitters of nerve endings and reduce conduction in C fibers. The reason that 0.1% capsaicin cream failed to inhibit the PGE2-evoked allodynia (Fig. 2A and 3A) was probably an unfavorable ratio of desensitization to irritation by topical application of a stronger capsaicin solution. In agreement with this study, in clinical studies, topical 0.025% capsaicin cream administration was beneficial in postherpetic neuralgia and postmastectomy pain syndrome (18,19). However, at increased concentrations, capsaicin-associated burning sensation can negate the beneficial effect.

We previously demonstrated that the PGE2-induced allodynia is mediated by the N-methyl-D-aspartate (NMDA) type of glutamate receptor and is blocked by morphine (14). Hyperalgesia and allodynia produced by intradermal capsaicin were relieved by the noncompetitive NMDA antagonist ketamine and opioids (20,21). Therefore, it is hypothesized that capsaicin applied topically penetrates to the subdermal layer and stimulates afferent activity in C fibers, which causes a release of glutamate, in addition to substance P, from the presynaptic terminals in the spinal cord. This results in central sensitization, possibly followed by functional desensitization without morphologic changes. In naive rat spinal cords, PGE2 levels were increased by substance P, NMDA, and capsaicin (22). Conversely, the addition of PGE2 to the culture medium stimulated the capsaicin-evoked substance P release from cultured dorsal root ganglion cells and spinal slice preparations (23,24). Glutamate is also released from capsaicin-sensitive afferent fibers in the spinal cord (25), and the release is stimulated from the spinal cord synaptosomes by PGE2 (26). The synthesis and release of PGE2 may feed back on primary afferent terminals to augment the evoked release of glutamate and neuropeptides. Topical application of capsaicin cream may break the positive feedback loop in the spinal cord and block the PGE2-induced allodynia. This study may partially explain the antiallodynic effect of capsaicin cream and provide a rationale for the use of capsaicin cream as a clinically therapeutic drug for pain relief.


   Acknowledgments
 
Supported, in part, by Grants-in-Aids for Scientific Research on Priority Areas, Scientific Research (B) (11558093 and 13470328), from the Ministry of Education, Science, Sports, and Culture of Japan and by grants from the Science Research Promotion Fund of the Japan Private School Promotion Foundation.

PGE2 and PGF2{alpha} were generous gifts from Ono Central Research Institute (Osaka, Japan). Capsaicin or vehicle cream was supplied by Maruishi Pharmaceutical Co., Ltd. (Osaka, Japan).


   References
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 Abstract
 Introduction
 Methods
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 Discussion
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Accepted for publication April 16, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press