Capsaicin: neuropathic pain relieving effect and neurotoxic effect
Abstract: Capsaicin seems to have quite complex neurochemical effect. While many still believe that it release the pain by decreasing the substance P level and use it as a treatment of neuropathic pain, it actually works by differentially modulation of substance P in pain pathways. Thus, it is the interaction between substance P and the particular receptor sites that causes either nociceptive or anti-nociceptive effect. Capsaicin not only affects the substance P level, but also nitric oxide level and activity of general proteases in calcium dependent manner. This might cause its neurotoxic effect. If this protease actually contributes to neurotoxicity of capsaicin in vivo, capsaicin's anti-nociceptive effect through the substance P might be thought as a result of degradation of substance P receptor rather than decrease in its concentration. Also there was an increase of nitric oxide level upon its administration. Since nitric oxide and its synthase production is also related to glutamate induced neurotoxicity, capsaicin's neurotoxic effect might work through enhancing the glutamate level or its activity. Thus, capsaicin has some neurotoxic effect while embodying useful medical benefits.
Nothing makes nachos better than hot and spicy jalapeno peppers. The variety of the color and pungency of peppers add more delicacy to many Asian dishes. A chemical in the white ribs of peppers called capsaicin, which the most peppers of the plant genus Capsicum contain, causes this pungency. Its natural function is to protect the plants from being eaten, but we humans take this warning as a delicacy, something that makes our choice in food all the better (www1). What is more remarkable is that capsaicin is a standard ingredient in over-the-counter drugs to relieve muscle pain and particular neuropathic pains. However, given the fact that capsaicin binds to vanilloid receptor in pain signal pathway, it is quiet amazing that it can actually relieve pain (Caterina et al. 1997).
Many placebo-controlled trials of capsaicin cream have done on cancer patients with surgical neuropathic pain, those with severe bladder pain, arthritis, psoriasis, or inflammatory bowel disease (www2). In a clinical trial done by Lazzeri, M. et al., the effectiveness of intravesical capsaicin in treatment for severe bladder pain was studied using a randomized placebo control. The patients with a diagnosis of interstitial cystitis had severe bladder pain as well as frequent nocturia (night urges) and urgency. The patients were randomly divided into several groups and given capsaicin mixed in saline (capsaicin group) or only saline (placebo group). To mimic the burning sensation of capsaicin, the placebo was heated before injection. Although such mimicked burning effect could not lasted long enough comparing to that of capsaicin, no significant number of patients could guessed which treatment group they were in. Both groups showed decrease in pain, however the groups that received capsaicin showed greater improvement. The pain reduction in the placebo-controlled group could be explained as "placebo effect." Also there was a slight but measurable increase in bladder capacity in the capsaicin group. However, symptoms of urgency were not reduced by the drug (www3). Thus, the capsaicin seems to work as pain reducer.
The researchers found out that capsaicin binds to nociceptors on afferent nerve endings of pain pathway, thus gives a pain sensation when administered. One might expect that stimulating them would cause more, not less, pain. Indeed, this is why initial use of capsaicin cream or other forms of capsaicin therapy produces burning sensation that lasts for some periods of time. However, continual stimulation of these nerves (continual application of such medications) produces a long-term reduction in the amount of pain they transmit. Many researchers have been trying to find out the mechanism of capsaicin's analgesic property. One common hypothesis is the desensitization, like what normally happens in many other drug uses: capsaicin overstimulation will cause down regulation in the number of capsaicin receptor or in the neurotransmitter released by capsaicin stimulation. Another common theory is the neurotoxic effect of capsaicin that causes nerve cell death, which then results in less sensitivity to pain.
Neurotoxicity of capsaicin
1) Involvement of calcium-activated proteases:
Capsaicin was found to exert a specific excitatory action on a subset of dorsal root ganglion neurons. It excites this particular neurons by activating a cation-specific ion channel that is permeable to wide range of cations, including divalents such as Co++ and Ca++. Application for capsaicin for prolonged periods of time can cause irreversible toxic effects leading to the loss of pain-sensing neurons. Although the mechanisms underlying capsaicin-mediated neuronal death are unknown, it has been shown that capsaicin causes a prolonged increase in calcium concentration. According to the recent hypothesis of excitotoxicity nerve cell death, this prolonged elevation in calcium concentration might be the first step in a sequence of events ultimately leading to the cell death. Chard, P.S. et al speculated that some calcium-dependent proteases play an important intermediate role connecting calcium concentration with cell death. Calpain is a protease that works in calcium-dependent manner. Its protease action results in the degradations of diverse cellular substrates including ion channels. Physiologically, it is found to play a role of regulating protein concentration and enzyme activity. However, when calcium homeostasis in the central nervous system is altered somehow, it might lead to excessive activation of calpain and thus subsequent cell death (Chard et al. 1995).
In their experiments, cell death could be prevented by the capsaicin receptor antagonist Ruthenium Red prior to and during capsaicin stimulation, and by removing extracellular calcium. Thus, it became clear that the capsaicin causes the cell death in calcium concentration dependent manner. When they examined whether the cell death produced after capsaicin treatment could be prevented by incubation with inhibitors of calcium-activated proteases, both the general protease inhibitor E64 and the synthetic calpain inhibitor MDL 28,170 markedly reduced the capsaicin-dependent cell death. This reduction in capsaicin-dependent cell death was not due to the calpain inhibitors acting at cation influx/release site, since neither E64 nor MDL 28170 blocked capsaicin-induced Co++ uptake. To ascertain whether capsaicin was stimulating calpain activity, they monitored the degradation of cytoskeletal protein (-spectrin, one of the preferred calpain substrate. Using an affinity-purified specific antibody, it was shown that natural calpain inhibitor did not make significant increase in calpain metabolite while synthetic MDL 28170 caused a significant increase in calpain metabolite measurement. It was probably E64, the naturally occurring inhibitor, is a general protease inhibitor having broad specificity and has poor membrane permeability that it is not suitable agent for rapid and selective inhibition of calpain in intact cells. However, they concluded that because capsaicin was no longer neurotoxic when external calcium was removed or when calcium-dependent protease activity was inhibited, capsaicin exerts its neurotoxic action as a consequence of increases in calcium concentration, which in turn causes the observed toxic effects via activation of proteases such as calpain (Chard et al. 1995).
2) Involvement of Nitric Oxide:
Nitric oxide synthase, which is constitutively expressed in some neurons, can be induced in other neurons by pathological conditions (Vizzard et al. 1995). The nitric oxide synthase expression in small to medium sized dorsal root ganglion neurons suggesting that this change might be limited to, or most prominent in, C-fiber afferents. These afferents are also very sensitive to the neurotoxin, capsaicin, which can deplete neuropeptide stores in C-fibers and in high doses cause degeneration of C-fiber afferent pathways (Bret-Dibat et al. 1997; Vizzard et al 1995). Vizzard et al. at University of Pittsburgh, School of Medicine performed the experiment to see whether a chemically induced injury elicited in small diameter afferent neurons by administration of capsaicin can induce a change in nitric oxide synthase expression. With nitric oxide synthase-immunoreactivity, they detected nitric oxide synthase following capsaicin pretreatment. A significant increase in the number of nitric oxide synthase-immunoreactive cells was detected in dorsal root ganglia. These results indicate that the expression of nitric oxide synthase-immunoreactivity in afferent neurons in the dorsal root ganglia can be upregulated in response to chemical stimulation. Thus, they thought that nitric oxide formed by enhanced expression of nitric oxide synthase may play a role in capsaicin-induced neurotoxicity (Vizzard et al. 1995).
Little after Vizzard et al. published their research, another research team proved that the nitric oxide synthase-containing neurons in sensory ganglia are susceptible to capsaicin-induced cytotoxitity. Although it was unknown whether nitric oxide itself plays a role in capsaicin-induced neurotoxicity, the loss of most nitric oxide synthase (+) neurons after neonatal capsaicin treatment suggested that the presence of nitric oxide synthase in dorsal root ganglion neurons does not act as a neuroprotectant for the Ca++-mediated capsaicin-induced cytotoxicity. Since most small dorsal root ganglion neurons are involved in nociception, nitric oxide may be involved in the functional plasticity of dorsal root ganglion neurons related to persistent pain, as well as the responses to nerve injury (Ren and Ruda 1995). More recent study support the fact that capsaicin induces the nitric oxide involved neurotoxicity. Wu et al. published their research such findings last year in Neuroreport. Their study provided direct evidence from measurements of its metabolites, nitrite and nitrate, that nitric oxide is released in the spinal cord during central sensitization. In other words, if nitric oxide production is increased, the amount of nitrite and nitrate production will also increase. A microdialysis fiber was implanted in the dorsal horn to collect dialysate (which contains nitric oxide metabolites) and administer drugs. The result was that after injection of capsaicin into on hind foot, nitrate increased in the dialysate. Pretreatment with NG-nitro-L-arginine methylester (L-NAME), the nitric oxide synthase inhibitor, significantly reduced nitric oxide release induced by a second injection of capsaicin into the opposite foot. This supports the ideas that nitric oxide is involved in central sensitization in the spinal cord and contributes to hyperalgesia and allodynia following capsaicin injection (Wu et al. 1998). In another study, when used a porphyrinic microsensor placed on the surface of urinary bladder strips in vitro to directly measure endogenous nitric oxide production, there was an evoked transient (1-3 sec) nitric oxide release upon the administration of the afferent neurotoxin, capsaicin. This release evoked by capsaicin was significantly decreased after urinary denervation. Thus, capsaicin releases nitric oxide from epithelium as well as nervous tissue in the urinary bladder. Nitric oxide may regulate epithelial integrity and function in other tissues. Agonist regulation of a constitutive nitric oxide synthase activity in the urinary bladder may provide a novel mechanism for modulation of bladder and urothelial function (Birder et al. 1998).
Although the precise mechanism of nitric oxide neurotoxic effect is still in study, its neurotoxicity has been known for a while. In 1992 publication on nitric oxide, Synder and Bredt suggest more complicated mechanism of nitric oxide with glutamate involvement. They observed that in cultures of cerebral cortical neurons, nitroarginie, a particularly potent and selective inhibitor of nitric oxide synthase, completely prevents the neurotoxicity elicited by NMDA (which binds to NMDA-glutamate excitatory calcium channel and leads to cell death). Also, hemoglobin, which binds with and thereby inactivates nitric oxide, also inhibits the toxic effects. Thus, nitric oxide is clearly responsible for the neurotoxicity produced by glutamate acting at NMDA receptors in the cultures. Since NMDA antagonists can block the glutamate-induced damage associated with vascular strokes, nitric oxide may also modulate neuronal destruction caused by stroke. It was also found that injection of small doses of nitroarginine into mice reduced stroke damage by 73 percent when administered immediately after initiating a stroke. Therefore, it was suggested that inhibitors of nitric oxide synthase may have therapeutic benefit in stroke and neurological damage associated with excess glutamate release (Snyder and Bredt 1992).
Capsaicin and substance P release:
Many still speculate that the change in substance P level results in anti-nociceptive function of prolonged exposure to capsaicin. Substance P is released after various nociceptive stimuli and following peripheral and intrathecal application of the pungent compound capsaicin. Although the mechanism is unknown, capsaicin is believed to increases substance P release initially, then significantly decrease the level when continuously introduced to cells. However, the changes in substance P level were showed to be dependent on the selection of the neuronal part of the study (Bret-Dibat et al. 1997). In this study, Bret-Dibat et al. found out that total spinal levels of substance P in rats were not affected by capsaicin treatment. When specific regions were examined, it was determined that thoracic levels were decreased by 15% with capsaicin treatment. Also, they mentioned that in another study, a 35 0epletion of substance P was found in the dorsal spinal cord, but no depletion of substance P was observed in the ventral half. Although capsaicin is generally thought to impair chemical and heat sensitivity through spinal afferent pathways, their experiment was not perfectly consistent with this hypothesis. Thus, they concluded that not all substance P containing neurons are affected by capsaicin treatment.
The studies on the relation with the substance P level and the pain perception have been done to find out better methods of pain relief. The very recent study shows that substance C not only promotes the pain perception, but also has anti-nociceptive properties (Goettl and Larson 1998). Both N- and C- terminal fragments of substance P have biological activity in nociceptive systems. However, while C-terminal activity is only associated with pro-nociception, N-terminal metabolites of Substance P exhibit both anti-nociceptive and pro-nociceptive (hyperalgesic) activity. The predominant N-terminal metabolite of Substance P, SP(1-7), has been found to be active in a dose-dependent manner in the writhing and formalin assays in mice. The acetic acid-induced writhing assay is a model for visceral pain which is more sensitive to the anti-nociceptive properties; and the formalin pain model is useful in assessing both acute and tonic nociceptive responses. Goettl, V.M. and Larson A.A. at the University of Minnesota Program in Neuroscience hypothesized, based on the findings that exogenous SP(1-7) modulates nociceptive responses in both an anti-nociceptive as well as pro-nociceptive fashion, the N-terminus of endogenously released Substance P, or an accumulation of SP N-terminal metabolites, might similarly affect nociceptive responses, suggesting an on-going modulatory role during pain transmission. To examine this possibility, the effect of the SP N-terminal antagonist, D-SP(1-7) was used. In writing assay, SP(1-7) produced a dose-dependent anti-nociceptive effect when injected intrathecally 30 min before injecting acetic acid into mice to induce the writhing. When SP(1-7) was co-injected with D-SP(1-7), however, anti-nociceptive effect was significantly reduced resulting the similar abdominal stretches count in writhing. In contrast to its effect in the writhing assay, low dose of SP(1-7) had no significant reducing effect on the number of behavior responses (licking and biting the paw after injection) upon formalin injection. However, low dose of D-SP(1-7) injected 5 min before formalin induced a dose-dependent hyperalgesia as acute response (phase I, 0-5 min). The pretreatment with SP(1-7) and D-SP(1-7) 24 hours before assay resulted in significant anti-nociceptive effect. Exogenously administered SP(1-7) can produce either antinociception or hyperalgesia, suggesting that SP N-terminal activity is brought about by an interaction at either of two distinct sites. Although the formalin and writhing assays were found to be differentially sensitive to a wide range of doses of D-SP(1-7), the site at which SP(1-7) appears to induce anti-nociception has a relatively high sensitivity to the inhibitory effects of D-SP(1-7) in both assays. The failure of low doses of D-SP(1-7) to produce hyperalgesia in the writhing assay indicates that acetic acid does not induce SP N-terminal activity at this site. Thus, the anti-nociceptive effect in the writhing assay is evident only after exogenously administered SP(1-7). In acute response of the formalin assay, low doses of D-SP(1-7) elicit hyperalgesic responses. These data suggest that formalin triggers the production of an endogenous pool of SP N-terminal fragments that interact with an anti-nociceptive N-terminal site (Goettl and Larson 1998).
What's more intriguing in their research is that capsaicin's anti-nociceptive effect is not due to the decrease in substance P release. Larson, with other research partners, showed that one nmol of D-SP(1-7) coadministered with capsaicin blocks the anti-nociceptive effect typically observed 24 hours later when tested using the writhing and hot plate assay (Kreeger 1994; Mousseau 1994). Based on this effect of D-SP(1-7), capsaicin-induced anti-nociception appears to result from the long-term effect of N-terminal metabolites formed following release of SP rather than from decreased release of SP or SP depletion. With parallel studies, they suggest that decrease in capsaicin-induced release of SP do occur, but not until well after the anti-nociceptive effect of capsaicin or SP(1-7) has developed, consistent with the conclusion that decreased release of SP cannot account for the anti-nociceptive effect of either capsaicin or SP(1-7). The ability of SP N-terminal fragments to modulate excitatory amino acid activity even for long periods of time may underlie the mechanism by which SP differentially modulates theses pain pathways (Goettl and Larson 1998).
In summary, the capsaicin seems to have quite complex neurochemical effect on our nervous system. While many still believe that it release the pain by decreasing the substance P level and use it as a treatment of neuropathic pain, it actually works by differentially modulation of substance P in pain pathways. Thus, it is the interaction between substance P and the receptor sites of particular that causes either nociceptive or anti-nociceptive effect. In addition, capsaicin not only affects the substance P level, but also nitric oxide level and activity of general proteases in calcium dependent manner. Since nitric oxide and its synthase production is also related to glutamate induced neurotoxicity, capsaicin's neurotoxic effect might work through enhancing the glutamate level or its activity. In addition, the increase in general endogenous protease activity due to capsaicin induced increase of Ca++ concentration cannot be ignored. If this protease actually contributes to neurotoxicity of capsaicin in vivo, capsaicin's anti-nociceptive effect through the substance P might be thought as a result of degradation of substance P receptor rather than decrease in its concentration. Capsaicin's property of increasing calcium and other cation concentration also need to be carefully examined in relation with glutamate-induced "excitotoxicity" since both seems to be related with increase of nitric oxide, the neurotoxin. The neurotoxicity of capsaicin, which might bring up long-term side effect of its medical use, still needs to be studied in more depth.
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WWW1. The Mystery of Capsaicin.
WWW2. Topical capsaicin NNTs [Jul 1996; 29-6]
WWW3. Intravesical capsaicin for treatment of severe bladder pain: A randomized placebo controlled study.
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