Wollina U.
The response of erythematous rosacea to ondansetron.
Br J Dermatol. 1999 Mar;140(3):561-2. No abstract available.
PMID: 10233299 [PubMed - indexed for MEDLINE]
"The response of erythematous rosacea to ondansetron
U. Wollina
Sir, Rosacea is one of the most common chronic dermatoses in adults. It affects the centrofacial skin and is characterized by flushing, persistent erythema, telangiectasias, episodes of inflammation with swelling, papules and pustules. Rosacea is not restricted to the skin but often affects the eyes, which is of prognostic importance. An association of rosacea and migraine has been
noted.1 The cause of rosacea is not known, but the basic abnormality seems to be microcirculatory. The neurotransmitter
substance P and neuropeptide vasoactive intestinal peptide have been shown to be elevated in a small series of patients. In rhinophyma, a special type of rosacea, an increase in vasoactive intestinal peptide receptor-positive dermal cells has been
observed.2, 3
A 56-year-old woman with stage I rosacea with telangiectasias, persistent oedema and erythema and severe eye involvement was treated with minocyline 50 mg/day. Topical therapy included 2.0% metronidazole cream. After a partial remission, the patient experienced a severe relapse, although she continued the treatment. In particular, she had severe eye involvement with a keratitis sicca and a cornea verticillata causing vertigo. Therefore, we decided to use the serotonin antagonist ondansetron (Zofran). During 4 days of intravenous therapy with ondansetron, 12 mg/day, the patient showed a tremendous improvement of the eye involvement and a partial remission of the cutaneous symptoms. About 2 weeks after treatment, she had a partial relapse, which promptly responded to oral ondansetron 8 mg twice daily.
Stimulated by this positive observation, a second 46-year old woman with corticoid-induced erythematous rosacea and lupus erythematosus was treated with ondansetron, 8 mg orally twice daily. She had some problems with minocyline-induced gastrointestinal side-effects and did not respond to topical metronidazole alone. During a 1-week course of treatment, the erythema improved markedly, and flushing decreased ( Fig. 1 ). Treatment was continued with 4 mg twice daily. Both patients tolerated the treatment very well. No unwanted side-effects were noted.
Treatment of rosacea is difficult. Topical agents are not as effective as in acne vulgaris. The systemic therapy of choice is minocycline for both cutaneous and ocular manifestations. Other antibiotics are in use. Oral isotretinoin may be appropriate for severe or therapy-resistant forms, but it has a higher risk of unwanted side-effects. Sobye's massage is of benefit in persisting oedemas.1 Ondansetron is a 5-hydroxytryptamine antagonist used in palliative therapy to prevent or treat chemotherapy- and vertigo-induced nausea and vomiting that can also suppress the associated
flush.4 It has also been reported that ondansetron inhibits the carotid chemoreflex, the baroreflex and the Bezold–Jarisch
reflex.5 Some of these effects are related to an antagonism of ondansetron to substance
P.6
In the past decades, several other vasoactive compounds have been used to block the flushing reaction. Clonidine hydrochloride, an agent effective in suppressing several types of flushing, was unable to suppress the induced flushing reaction in rosacea but caused malar hypothermia.
Wilkin7 suggested that the beneficial effect of clonidine hydrochloride might be related to the reduction in vascular reactivity. Naloxone blocked the alcohol-induced flushing reaction in rosacea, suggesting an active role of endogenous neuropeptides in vascular
hyperreactivity.8 I observed a prompt and substantial response of persistent erythema and flushing in rosacea to a serotonin 3 receptor antagonist. Although anecdotal, the present paper provides further evidence for rosacea as a primary vascular disease and offers a new therapeutic option.
Wilkin JK.
Flushing reactions: consequences and mechanisms.
Ann Intern Med. 1981 Oct;95(4):468-76. Review.
PMID: 6169300 [PubMed - indexed for MEDLINE]
Kurkcuoglu N, Alaybeyi F.
Substance P immunoreactivity in rosacea.
J Am Acad Dermatol. 1991 Oct;25(4):725-6. No abstract available.
PMID: 1724248 [PubMed - indexed for MEDLINE]
Powell FC, Corbally N, Powell D.
Substance P and rosacea.
J Am Acad Dermatol. 1993 Jan;28(1):132-3. No abstract available.
PMID: 7678842 [PubMed - indexed for MEDLINE]
This article is referenced in Dr. Nase's book along with a few other Substance P developments. He
mentioned another doc having success treating rosacea patients with Zofran. I am most surprised by the
rapid onset of benefits & reported benefits on ocular rosacea.
Constipation is considered the most common side effect & can be a
significant issue for this antiemetic drug. Another major drawback
is a price of $15-$40 a pill in the USA currently, often less than half this
price abroad like at http://www.canadameds.com
(price likely based on lower volume sales of limited indications & the country's price regulations).
*Cautionary Note About EPS/side effects*
There are much more powerful and specific Substance P antagonists in
development that could prove more effective, tolerable and certainly affordable. I have
heard that Merck's original drug MK-869 referenced in Dr. Nase's book will be going for the
same market as Zofran while they develop an even more specific, potent substance P
drug for depression, anxiety & pain.
Many drugs don't mention their effects on substance P mainly because there aren't ones whose primary
pharmacological actions are on it. Maxalt a migraine medication also doesn't mention in the PDR (like
Zofran) effects on substance P but has indicated in part effects on Substance P under hypothesized mechanisms of
action in research studies.
There are other medications that have similar serotonin 3 receptor antagonist
effects as Zofran (indicated as the primary pharmacological mechanism of action)
among their other varied effects but have not been reported to date to have such
a rosacea & ocular rosacea response so it may be the antagonism of substance
P.
Substance P is better known as a neurotransmitter of pain that is released by
topical analgesic capsaicin creams like Zostrix (made from hot peppers) which
initially cause erythema/vasodilation & burning sensations as substance P is
released from neurons. The reason it is used as an analgesic (&
studied in inflammatory skin disorders like psoriasis) is because after repeated
applications, substance P is depleted. With antagonists (instead of
releasers) the initial irritating skin effects should not be an issue &
better suited for rosacea.
cap·si·cum
(kăpʹsĭ-kəm)
noun
1.
Any of various
tropical American pepper plants of the genus Capsicum, especially any
of the numerous cultivated forms of the species C. annuum and C.
frutescens.
2. The
fruit of any of these plants, especially the dried pungent types used as a
condiment and in medicine.
cap·sa·i·cin
(kăp-sāʹĭ-sĭn)
noun
A colorless, pungent, crystalline compound,
C18H27NO3, that is derived from capsicum and is a strong irritant to skin and
mucous membranes (as is the conjunctiva of the eye often involved in ocular
rosacea conjuctivitis).
Ondansetron: a selective 5-ht(3) receptor antagonist
and its applications in cns-related disorders.
Ye JH, Ponnudurai R, Schaefer R.
Department of Anesthesiology, UMDNJ-New Jersey Medical School, 185 South
Orange Avenue, Newark, NJ 07103, USA. ye@umdnj.edu
Ondansetron is a selective 5-hydroxytryptamine(3) (5-HT(3)) receptor
antagonist that has been introduced to clinical practice as an antiemetic
for cancer treatment-induced and anesthesia-related nausea and vomiting.
Its use under these circumstances is both prophylactic and therapeutic. It
has a superior efficacy, safety and pharmacoeconomic profile compared with
other groups of antiemetics, namely antidopaminergics, antihistamines and
anticholinergics. However, its place in the management of anticipatory and
delayed vomiting in cancer treatment and as a rescue antiemetic in
surgical patients needs to be further explored. Furthermore, recent
animal and human research also reflects its possible novel application in
the treatment of other disease states, such as alcoholism, cocaine
addiction, opioid withdrawal syndrome, anxiety disorders, gastrointestinal
motility disorders, Tourette's syndrome and pruritus. This review
revisits the widespread physiological and pathological effects of 5-HT and
discusses both the basic science literature and the clinical developments
responsible for the conventional and novel uses of ondansetron. In
addition, new discoveries relating to the effects of ondansetron on other
receptors/channels and their possible therapeutic applications are
presented.
Inhibition by 5-HT3 receptor antagonists of release of
cholecystokinin-like immunoreactivity from the frontal cortex of freely
moving rats.
Raiteri M, Paudice P, Vallebuona F.
Istituto di Farmacologia e Farmacognosia, Universita degli Studi di Genova,
Italia.
Effects of the 5-HT3 receptor antagonists, ondansetron and
tropisetron, on the release of cholecystokinin-like immunoreactivity (CCK-LI)
in rat frontal cortex were investigated in conscious, unrestrained rats
using intracerebral microdialysis. The release of CCK-LI was augmented by
perfusion with 100 micrograms/ml veratrine and was fully Ca(2+)-dependent
and tetrodotoxin-sensitive. Ondansetron and tropisetron, each at 0.1-1
mumol/l, decreased concentration-dependently the veratrine-evoked efflux
of CCK-LI. The reduction of CCK-LI output was approximately 30% when the
antagonists were infused at 0.1 mumol/l. The data suggest that 5-HT3
receptor antagonists prevent the release of CCK evoked by endogenous
5-hydroxytryptamine. These drugs may thus represent a novel
therapeutic approach in disease states, like anxiety, in which an
inappropriately high release of brain CCK or 5-hydroxytryptamine seems to
be involved.
Antianxiety profile of ondansetron, a selective 5-HT3
antagonist, in a novel animal model.
Roychoudhury M, Kulkarni SK.
Pharmacology Division, Panjab University, Chandigarh, India.
The profile of action of ondansetron was assessed in a novel animal
model of anxiety. The mirrored chamber is a nonpunishing quantitative
model of anxiety which measures approach-conflict behavior. Ondansetron in
all the doses tested (0.01, 0.1 and 1 mg/kg i.p.) showed significant
anxiolytic action as compared to naive mice, but it was less
potent as compared to a well-known anxiolytic, diazepam (1 mg/kg). These
results suggest that ondansetron has anxiolytic efficacy in nonconflict
paradigms of anxiety, a response not mediated by the conventional
neurotransmitter receptors. GABA-benzodiazepine as flumazenil (4 mg/kg), a
benzodiazepine receptor antagonist, failed to reverse the behavioral
parameters evoked by ondansetron.
Treatment of acute gouty arthritis with the
5-hydroxytryptamine antagonist ondansetron.
Schworer H, Ramadori G.
Abteilung Gastroenterologie und Endokrinologie, Medizinische
Universitatsklinik, Gottingen, Germany.
We report on a 28-year-old man with hematemesis, renal dysfunction, and
arterial hypertension who suffered from an acute gouty attack presenting
as podagra. Because of the accompanying symptoms conventional treatment of
the gouty attack with colchicine or nonsteroidal anti-inflammatory drugs
was contraindicated. We treated the pain of acute arthritiswith
the specific 5-hydroxytryptamine subtype 3 receptor antagonist ondansetron.
Within 30 min after intravenous injection of this drug a substantial
degree of pain relief had occurred. Unwanted side effects due to
treatment were not observed. It is suggested that the 5-hydroxytryptamine
released during a gouty attack induces pain via activation of 5-hydroxytryptamine
subtype 3 receptors on nociceptive afferent nerve fibers.
5-Hydroxytryptamine subtype 3 receptor antagonists may therefore be a
novel class of drugs for the effective treatment of acute gouty attacks
when conventional treatment is contraindicated.
Effects of peripheral stem cell or bone marrow
reinfusion on peripheral serotonin metabolism.
Wymenga AN, van der Graaf WT, Kema IP, Smit Sibinga CT, Vries EG,
Mulder NH.
Department of Medical Oncology, University Hospital Groningen, The
Netherlands.
Reinfusion of autologous hematopoietic peripheral blood stem
cells (PBSC) or bone marrow is often accompanied by flushing,
dyspnea, abdominal cramping, nausea and diarrhea. These
symptoms and the observation that they can be prevented by
ondansetron, a selective 5-HT3 receptor antagonist, led to the
assumption that these side-effects are due to infusion of free serotonin
during the reinfusion of PBSC or bone marrow. Twenty-five patients with
solid tumors received, after myeloblative chemotherapy, a total of 30
reinfusions of PBSC and/or bone marrow. In 17 patients, serotonin levels
in the bags containing the PBSC were measured. In all patients, platelet
serotonin levels were determined before and 1 h post-reinfusion. In
addition, before and 24 h after reinfusion urine was collected for
determination of 5-hydroxyindole acetic acid (5-HIAA) and serotonin
concentrations. Mean (+/- s.d.) total serotonin concentration in the
bags was 2404 +/- 1555 nmol/l. Mean total volume reinfused was 471 +/-
185 ml. After reinfusion, the mean (+/- s.d.) levels of serotonin in
platelets in patients increased from 3.2 +/- 1.4 nm/10(9) at baseline to
3.8 +/- 2.0 nm/10(9) (P = 0.02). Neither 24 h urinary 5-HIAA nor
serotonin levels were affected. These results indicate that reinfusion
of PBSC or bone marrow is accompanied by substantial infusion of free
serotonin, which might explain the observed side-effects and justify the
use of 5-HT3 receptor antagonists as pre- medication for this procedure.
Ondansetron exhibits the properties of a local
anesthetic.
Ye JH, Mui WC, Ren J, Hunt TE, Wu WH, Zbuzek VK.
Department of Anesthesiology, University of Medicine and Dentistry of
New Jersey, Newark 07103-2714, USA. ye@umdnj.edu
The purpose of this study was to determine whether ondansetron (OND) has
local anesthetic effects. Using a patch-clamp technique, we showed that OND
concentration dependently blocked Na channel currents in freshly
isolated neurons of rat brains with a 50% inhibition concentration of 12
microM. The blockade started immediately when OND was applied to the
cell body using a fast perfusion system, reached a plateau within 15 s,
and recovered to the control level within 30 s after washout of the OND-containing
solution. Because this is a known property of local anesthetics, we used
the tail-flick technique to verify this effect in vivo in Sprague-Dawley
rats (n = 46). OND was injected subcutaneously into the tail at the
doses of 0.08, 0.16, and 0.2 mg. The tail-flick latency increased 2 min
after OND injection, reaching the plateau within 5 min. This effect was
dose-related, lasting from 10 to 25 min. These preliminary data indicate
that OND, a selective 5-HT3 receptor antagonist, might serve as a
prototype molecule for development of a novel series of local
anesthetics. IMPLICATIONS: Ondansetron is a drug used to prevent
vomiting, especially in cancer patients after chemotherapy. We found
that it also causes numbness when injected under the skin.
This new action may contribute to its role in "calming the
stomach." We studied the effect of ondansetron on the isolated
brain cells of live rats.
Rhinophyma--unusual expression of simple-type keratins
and S100A in sebocytes and abundance of VIP receptor-positive dermal
cells.
Wollina U.
Department of Dermatology, Friedrich Schiller University Jena, Germany.
Rhinophyma represents a severe variant of rosacea, a common mid-facial
erythematous dermatosis. Increased blood flow and pooling in skin are
thought to be involved in its pathogenesis. Since neuropeptides and
their receptors are responsible for local blood flow regulation,
immunolocalization for the vasoactive intestinal peptide (VIP)-receptor(R)
was performed in slice biopsies taken from five patients with glandular
rhinophyma. Additional immunostainings included intermediate filaments
(keratin, vimentin) and neuroglandular antigen (NGA). In contrast to
controls, rhinophyma disclosed not only a more dense distribution of VIP-R
positive cells within the endothelium but immunoreactive perivascular
large cells. The immature sebocytes stained positive with monoclonal
antibody Cam5.2 against glandular antigens and polyclonal anti-S100A.
Elastotic connective tissue in the dermis showed a strong immunoreactivity
for vimentin and NGA. From these results we suggest that, (a) ligands
of the VIP-R may contribute to vascular and dermal alterations in rosacea
and (b) immature sebocytes show an unusual antigen expression of S100A and
glandular keratin.
Ondansetron. A review of its pharmacology and
preliminary clinical findings in novel applications.
Wilde MI, Markham A.
Adis International Limited, Auckland, New Zealand.
The use of ondansetron, a selective serotonin 5-HT3 receptor antagonist,
is well established in patients with nausea and vomiting associated with
cancer chemotherapy, radiotherapy or anaesthesia and surgery. The wide
distribution of 5-HT3 receptors in the body and the role of these
receptors in disease have provided the rationale for investigation of ondansetron
in novel applications. Preliminary data have shown ondansetron to have
clinical benefit in patients with nausea and vomiting associated with drug
overdosage or poisoning, anti-infective or antidepressant therapies,
uraemia or neurological trauma, and in patients with pruritus. Patients
with gastrointestinal motility disorders (e.g. carcinoid syndrome,
irritable bowel syndrome, diarrhoea associated with cryptosporidiosis or
diabetes, and chronic refractory diarrhoea) have also shown some
improvement when treated with ondansetron, as have patients with certain
pain or CNS-related disorders [e.g. alcohol (ethanol)
dependence,
opiate withdrawal, vertigo, cerebellar tremor and Parkinson's disease
treatment-related psychosis]. In contrast to conventional antiemetics, ondansetron
is generally well tolerated with a lower incidence of sedation and only
isolated case reports of extrapyramidal reactions. Furthermore, unlike
dopamine receptor-blocking neuroleptics, ondansetron does not appear to
worsen the symptoms of Parkinson's disease. Thus, in addition to its
established indications, preliminary results suggest that ondansetron may
be beneficial in a number of novel applications. This drug may represent a
treatment alternative in patients with refractory disease, or an effective
treatment of conditions for which current therapies are either poorly
tolerated or not available. Further investigation of ondansetron in a
range of potential new applications appears to be warranted.
Role of serotonin3 receptors in the nucleus tractus
solitarii on the carotid chemoreflex.
Sevoz C, Callera JC, Machado BH, Hamon M, Laguzzi R.
Institut National de la Sante et de la Recherche Medicale, Unite 288,
Centre Hospitalier Universitaire Pitie-Saltpetrire France.
The effects of serotonin3 (5-HT3)-receptor stimulation in the
nucleus tractus solitarii (NTS) on the cardiovagal, sympathetic, and
respiratory responses to activation of carotid body chemoreceptors
were investigated in anesthetized rats. The chemoreflex responses were
triggered by an intravenous administration of KCN (40 microg/kg) in
spontaneously breathing urethan-chloralose-anesthetized rats or by an
intracarotid administration of saline saturated with 100% CO2 in
pancuronium bromide-paralyzed and artificially ventilated urethan-anesthetized
rats. Microinjections of 5-HT (2.5-5 nmol) or the 5-HT3 agonist 1-(m-chlorophenyl)-biguanide
(CPBG, 300-1,200 pmol) into the commissural NTS blocked in a
dose-dependent manner the atropine-sensitive chemoreflex bradycardia
elicited by KCN. However, neither 5-HT nor CPBG affected the KCN-induced
increase in respiratory volume and the CO2-induced increases in blood
pressure and lumbar sympathetic nerve discharge. The inhibitory effect of
5-HT or CPBG on KCN-induced bradycardia was blocked by prior intra-NTS
microinjection of a 5-HT3 antagonist, such as zacopride (100 pmol) or
ondansetron (100 pmol), or the A-type gamma-aminobutyric acid (GABA(A))
antagonist bicuculline (10 pmol). In contrast, local microinjections of
antagonists acting at 5-HT1 and 5-HT2 receptors, such as methysergide (100
pmol) and ketanserin (10 pmol), respectively, did not prevent the actions
of 5-HT or CPBG. These data show that the stimulation of 5-HT3
receptors in the NTS exerted an inhibitory influence, probably through the
activation of a local GABAergic system, on the cardiovagal component of
the chemoreflex. Because similar effects of 5-HT3-receptor stimulation
in the NTS were previously found on the baroreflex and Bezold-Jarisch
reflex responses, it can be inferred that NTS 5-HT3 receptors play a key
modulatory role in the reflex control of the heart rate.
The influence of substance P 3 (microgram/kg) and (+)-tubocurarine
(850 micrograms/kg) on the Bezold-Jarisch reflex in urethane-anaesthetized
rats was studied. The Bezold-Jarisch reflex was induced by the 5-HT3
receptor agonistphenylbiguanide (0.3, 1, 3 and 10
micrograms/kg i.v.) and by capsaicin (10 micrograms/kg i.v.). The
5-HT3 receptor antagonist ondansetron (10 micrograms/kg) abolished
the phenylbiguanide- but not the capsaicin-stimulated bradycardia,
indicating that phenylbiguanide and capsaicin act via different trigger
mechanisms (5-HT3 receptor-dependent and -independent, respectively). Substance
P significantly potentiated the phenylbiguanide- but not the
capsaicin-induced decrease in heart rate. Also, when the
phenylbiguanide-induced response was amplified by substance P, it
was abolished by ondansetron. (+)-Tubocurarine inhibited the
phenylbiguanide-induced bradycardia, but did not affect the
capsaicin-stimulated decrease in heart rate. Our results demonstrate
that substance P potentiates but (+)-tubocurarine inhibits the 5-HT3
receptor-mediated Bezold-Jarisch reflex. Both effects are probably due to
direct influences of the drugs on the 5-HT3 receptors on sensory vagal
nerves in the heart.
Preclinical and clinical pharmacology of the 5-HT3
receptor antagonists.
Wolf H.
Dept. of Clinical Research, Novartis Pharma GmbH, Nuremberg, Germany.
5-HT3-receptor antagonists are potent and highly selective competitive
inhibitors of the 5-HT3-receptor with negligible affinity for other
receptors. They are rapidly absorbed and penetrate the blood-brain
barrier easily. 5-HT3-receptor antagonists are metabolized by diverse
subtypes of the cytochrome P450-system, metabolites are excreted
mainly in urine. Half-lifes in healthy subjects vary from 3-4 hours (ondansetron,
granisetron) to 7-10 hours (tropisetron, hydrodolasetron).
5-HT3-receptor antagonists do not modify any aspect of normal
behaviour in animals or induce remarkable changes of physiological
functions in healthy subjects. They are well tolerated over wide dose
ranges, most common side effects in clinical use are headache and
obstipation. Clinical efficacy was first established in
chemotherapy-induced emesis. In this indication, 5-HT3-receptor
antagonists set a new standard regarding efficacy and tolerability.
Further established indications are radiotherapy-induced and
post-operative emesis. Antiemetic efficacy results from a simultaneous
action at peripheral and central 5-HT3-receptors. Other peripheral
actions include reduction of secretion and diarrhea caused by
increased intestinal serotonin content (e.g. in carcinoid syndrome), a
limited antiarrhythmic activity and a reduction of experimentally
induced pain. CNS effects comprise anxiolysis, attenuation of
age-associated memory impairment, reduction of alcohol consumption in
moderate alcohol abuse and an antipsychotic effect in patients with
parkinson psychosis. In migraine, 5-HT3-receptor antagonists show
moderate efficacy, as well. Repeatedly demonstrated efficacy of
5-HT3-receptor antagonists in patients suffering from fibromyalgia
raises the question for the mechanism of action involved. Ligand
binding at the 5-HT3-receptor causes manifold effects on other
neurotransmitter and neuropeptide systems. In particular, 5-HT3-receptor
antagonists diminish serotonin-induced release of substance
P from C-fibers and prevent
unmasking of NK2-receptors in the presence of serotonin. These
observations possibly provide an approach for the causal explanation
of favourable treatment results with 5-HT3-receptor antagonists in fibromyalgia.
(another condition associated with increased levels of substance P).
Effect of subdepressor clonidine on flushing reactions
in rosacea. Change in malar thermal circulation index during provoked
flushing reactions.
Wilkin JK.
The effects of clonidine hydrochloride, an agent effective in
suppressing other types of flushing reactions, were investigated in
patients with erythematotelangiectatic rosacea. Clonidine hydrochloride,
0.05 mg, was given orally twice daily for two weeks. Mean arterial BP was
not altered during clonidine treatment. Flushing reactions provoked with
water at 60 degrees C, red wine, and chocolate were not suppressed during
clonidine treatment. Clonidinedid lead to malar hypothermia. It
may be that any treatment benefit obtained from the reduction in
vascular reactivity by clonidine in rosacea is offset by the malar
hypothermia.
Alcohol-induced rosacea flushing blocked by naloxone.
Bernstein JE, Soltani K.
We evaluated the roles of endogenous opioid peptides and histamine in
the pathophysiology of alcohol-induced facial flushing in rosacea.
Non-diabetic patients with rosacea ingested 360 ml of 6% ethanol after
receiving either subcutaneous naloxone hydrochloride or oral
chloropheniramine maleate. Only pretreatment with naloxone blocked the
Alcohol-Induced Rosacea Flushing (AIRF), suggesting an active role
of endogenous enkephalin and/or endorphin in this vascular reactivity.
In this respect, AIRF is similar to chlorpropamide alcohol flushing and
menopausal flushing.
The A-Delta Fiber pain pathway carries information away from damaged skin
tissue at a rapid rate. This information reflects the sharp pain experienced
almost immediately following damage to the skin.
The C Fiber pain pathway carries information away from damaged skin tissue
at a slow pace. This information reflects the burning and aching sensation
associated with prolonged pain following damage.
