Selective degeneration by capsaicin of a subpopulation of primary sensory neurons in the adult rat

doi:10.1016/0304-3940(85)90201-0

Neuroscience Letters

Volume 59, Issue 2, 30 August 1985, Pages 209-214

https://doi.org/10.1016/0304-3940(85)90201-0 Get rights and content

Abstract

The morphological effects of systemic capsaicin treatment have been studied in adult rats. Light and electron microscopy revealed that a subpopulation of small-to-medium sized B-type primary sensory neurons, representing about 17% of the total neuronal population in the 4th lumbar spinal ganglion, underwent rapid degeneration after the administration of capsaicin. Quantitative electron microscopy demonstrated a decrease of about 45% in the number of unmyelinated axons in the saphenous nerve. Light microscopy showed extensive axon terminal degeneration in the brainstem and spinal cord confined to the central projection areas of capsaicin-sensitive afferent fibers, as has already been revealed in the newborn rat. The present results furnish evidence for a hitherto unrecognized selective neurodegenerative action of capsaicin in the adult rat.

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Cited by (207)

Fight fire with fire: Neurobiology of capsaicin-induced analgesia for chronic pain
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Capsaicin, the pungent ingredient in chili peppers, produces intense burning pain in humans. Capsaicin selectively activates the transient receptor potential vanilloid 1 (TRPV1), which is enriched in nociceptive primary afferents, and underpins the mechanism for capsaicin-induced burning pain. Paradoxically, capsaicin has long been used as an analgesic. The development of topical patches and injectable formulations containing capsaicin has led to application in clinical settings to treat chronic pain conditions, such as neuropathic pain and the potential to treat osteoarthritis. More detailed determination of the neurobiological mechanisms of capsaicin-induced analgesia should provide the logical rationale for capsaicin therapy and help to overcome the treatment's limitations, which include individual differences in treatment outcome and procedural discomfort. Low concentrations of capsaicin induce short-term defunctionalization of nociceptor terminals. This phenomenon is reversible within hours and, hence, likely does not account for the clinical benefit. By contrast, high concentrations of capsaicin lead to long-term defunctionalization mediated by the ablation of TRPV1-expressing afferent terminals, resulting in long-lasting analgesia persisting for several months. Recent studies have shown that capsaicin-induced Ca²⁺/calpain-mediated ablation of axonal terminals is necessary to produce long-lasting analgesia in a mouse model of neuropathic pain. In combination with calpain, axonal mitochondrial dysfunction and microtubule disorganization may also contribute to the longer-term effects of capsaicin. The analgesic effects subside over time in association with the regeneration of the ablated afferent terminals. Further determination of the neurobiological mechanisms of capsaicin-induced analgesia should lead to more efficacious non-opioidergic analgesic options with fewer adverse side effects.
Role of capsaicin sensitive sensory nerves in ischemia reperfusion-induced acute kidney injury in rats
2018, Biochemical and Biophysical Research Communications
Citation Excerpt :
In this study, although capsaicin can directly act on adult rats resulting in selective degeneration of primary sensory neurons, SD neonatal rats were chosen to take capsaicin treatment for denervation of afferent sensory nerves. The reason is that capsaicin given to newborn rats would result in an irreversible loss of specific sensory functions, with a greater proportion reduction in the numbers of dorsal root ganglion neurons and unmyelinated axons, as compared with that of adult rats taking such treatment [25,26]. There are also other methods to achieve renal denervation.
Acute kidney injury (AKI) is a common kidney disorder which is associated with a high risk of mortality. Extensive evidence revealed the participation of renal afferent sensory nerves in the pathophysiology of renal ischemia reperfusion (IR) injury, however the role of these nerves in renal IR injury is controversial and remains to be further explored. Here, we report that capsaicin sensitive sensory nerves and neuropeptides prevented renal damage in AKI induced by IR injury. The sensory afferent degeneration model was established by injecting 50 mg/kg of capsaicin to male neonatal rats and verified by the tail flick test and reduced sensory neuropeptide of substance P and calcitonin gene related peptide in spinal cord, dorsal root ganglion and kidney after 12 weeks. Then, a model of renal IR injury was established. The sensory afferent degeneration in the AKI group increased the level of serum creatinine, NGAL and KIM-1, aggravated to some extent renal pathological damage, and enhanced the proinflammatory cytokines expressions and tubular cell apoptosis. In addition, it was also discovered that the level of phospho-ERK/ERK (p-ERK/ERK) showed an increase in spinal cord and kidney after degeneration of capsaicin sensitive sensory nerves. In conclusion, the degeneration of sensory nerves aggravated IR-induced AKI in rats, and the activated ERK signaling in spinal cord and kidney after sensory afferent degeneration might be the possible mechanism in the aggravated renal injury.
Sensory denervation of inguinal white fat modifies sympathetic outflow to white and brown fat in Siberian hamsters
2018, Physiology and Behavior
Citation Excerpt :
We measured NETO in WAT depots and IBAT of hamsters that had IWAT sensory denervation using CAP, the pungent component of red chili peppers. CAP chemically destroys sensory nerves and is more specific than surgical denervation where both SNS or sensory nerves are likely to be severed due to their close proximity to each other [30,34,35,44,45]. Unchanged TH staining in CAP injected WAT verified CAP's specificity for destroying afferents [35,46].
White adipose tissue (WAT) and brown adipose tissue (BAT) have sympathetic nervous system (SNS) and sensory innervations. Previous studies from our laboratory revealed central neuroanatomical evidence of WAT sensory and BAT SNS crosstalk with double labeling of inguinal WAT (IWAT) sensory and interscapular BAT (IBAT) SNS neurons. We previously demonstrated that WAT lipolysis increases IBAT temperature, but this effect is absent when IWAT afferents are surgically denervated, which severs both sensory and SNS nerves. It is possible that WAT sensory feedback can regulate SNS drive to itself and other WAT and BAT depots, and thus contribute to the existence of differential SNS outflow to fat during different energy challenges. Here we selectively denervated IWAT sensory nerves in Siberian hamsters using capsaicin and measured norepinephrine turnover (NETO) i.e., SNS drive to WAT and BAT depots, IBAT uncoupling protein 1 (UCP1) expression, body mass, fat mass, blood glucose, and food consumed after a 24-h cold exposure. IWAT sensory denervation decreased both IWAT and IBAT NETO and IBAT UCP1 expression. IWAT sensory denervation, however, increased mesenteric WAT (MWAT) NETO after the 24-h cold exposure and did not modify epididymal WAT (EWAT) and retroperitoneal WAT (RWAT) NETO compared with respective controls. Body mass, fat mass, blood glucose, and food consumed were unchanged across groups. RWAT and EWAT mass decreased in capsaicin-injected hamsters, but did not in the vehicle hamsters. These results functionally demonstrate the existence of IWAT sensory and IBAT SNS crosstalk and that a disruption in this sensory-SNS feedback mechanism modifies SNS drive to IWAT, IBAT, and MWAT, but not EWAT and RWAT.
Analysis and measurement of the sympathetic and sensory innervation of white and brown adipose tissue
2014, Methods in Enzymology
Here, we provide a detailed account of how to denervate white and brown adipose tissue (WAT and BAT) and how to measure sympathetic nervous system (SNS) activity to these and other tissues neurochemically. The brain controls many of the functions of WAT and BAT via the SNS innervation of the tissues, especially lipolysis and thermogenesis, respectively. There is no clearly demonstrated parasympathetic innervation of WAT or the major interscapular BAT (IBAT) depot. WAT and BAT communicate with the brain neurally via sensory nerves. We detail the surgical denervation (eliminating both innervations) of several WAT pads and IBAT. We also detail more selective chemical denervation of the SNS innervation via intra-WAT/IBAT 6-hydroxy-dopamine (a catecholaminergic neurotoxin) injections and selective chemical sensory denervation via intra-WAT/IBAT capsaicin (a sensory nerve neurotoxin) injections. Verifications of the denervations are provided (HPLC-EC detection for SNS, ELIA for calcitonin gene-related peptide (proven sensory nerve marker)). Finally, assessment of the SNS drive to WAT/BAT or other tissues is described using the alpha-methyl-para-tyrosine method combined with HPLC-EC, a direct neurochemical measure of SNS activity. These methods have proven useful for us and for other investigators interested in innervation of adipose tissues. The chemical denervation approach has been extended to nonadipose tissues as well.
Mechanism of capsaicin receptor TRPV1-mediated toxicity in pain-sensing neurons focusing on the effects of Na+/Ca2+ fluxes and the Ca2+-binding protein calretinin
2013, Biochimica et Biophysica Acta - Molecular Cell Research
Citation Excerpt :
Depending on the concentration applied and the exposure time, TRPV1 agonists cause either desensitization [21] or selective degeneration of a distinct population of primary sensory neurons involved in the mediation of pain [22]. Systemic administration of CAPS results in the death of approximately 50% of sensory neurons in rat neonates [13] and in a loss of approximately 17% in adult rats [23]. RTX, an ultrapotent CAPS analogue, almost completely eliminates TRPV1-expressing afferent neurons in adult rats, when applied systemically [24].
Transient receptor potential vanilloid subtype 1 (TRPV1) receptor is a pain-sensing, ligand-gated, non-selective cation channel expressed in peripheral sensory neurons. Prolonged activation of TRPV1 by capsaicin leads to cell swelling and formation of membrane blebs in rat dorsal root ganglion (DRG) neurons. Similar results were obtained in NIH3T3 fibroblast cells stably expressing TRPV1. Here, we assessed the contribution of Ca^2 + and Na⁺ ions to TRPV1-mediated changes. Cell swelling was caused by a substantial influx of extracellular Na⁺ via TRPV1 channels, causing concomitant transport of water. In the absence of extracellular Na⁺, the membrane blebbing was completely inhibited, but Ca^2 + influx did not change under these conditions. Na⁺ influx was modulated by the intracellular Ca^2 + concentration ([Ca^2 +]_i). Elevation of [Ca^2 +]_i by ionomycin sensitized/activated TRPV1 channels causing cell swelling in TRPV1-positive cells. In the absence of extracellular Ca^2 +, capsaicin caused only little increase in [Ca^2 +]_i indicating that the increase in [Ca^2 +]_i observed after capsaicin application is derived essentially from extracellular Ca^2 + and not from internal Ca^2 + stores. In the absence of extracellular Ca^2 + also the process of cell swelling was considerably slower. Calretinin is a Ca^2 + buffer protein, which is expressed in a subset of TRPV1-positive neurons. Calretinin decreased the amplitude, but slowed down the decay of Ca^2 + signals evoked by ionomycin. Cells co-expressing TRPV1 and calretinin were less sensitive to TRPV1-mediated, capsaicin-induced volume increases. In TRPV1-expressing NIH3T3 cells, calretinin decreased the capsaicin-induced Ca^2 + and Na⁺ influx. Swelling and formation of membrane blebs resulted in impaired plasma membrane integrity finally leading to cell death. Our results hint towards a mechanistic explanation for the apoptosis-independent capsaicin-evoked neuronal loss and additionally reveal a protective effect of calretinin; we propose that the Ca^2 +-buffering capacity of calretinin reduces the susceptibility of calretinin-expressing DRG neurons against cell swelling/death caused by overstimulation of TRPV1 channels. This article is part of a Special Issue entitled:12th European Symposium on Calcium.
Tachykinin (NK1, NK2 and NK3) receptor, transient receptor potential vanilloid 1 (TRPV1) and early transcription factor, cFOS, mRNA expression in rat tissues following systemic capsaicin treatment
2013, Regulatory Peptides
Citation Excerpt :
No significant changes in the brain stem and frontal cortex message were apparent. The original studies of Jancso and colleagues [26] reported degeneration of ~ 30% of sensory neurons in the rat saphenous nerve at the dose employed in the present study. Whilst degeneration may have contributed in part to the changes that we observed, one would have expected consistent changes in tachykinin receptor and TRPV1 mRNA expression in tissues known to be supplied by capsaicin-sensitive neurons.
Capsaicin, the pungent component of chilli pepper, stimulates TRPV1-expressing cells which are followed by desensitisation to subsequent exposure to capsaicin and other TRPV1 activators. At high systemic doses (> 125 mg/kg), capsaicin produces long-term changes in both tachykinin receptor and TRPV1 expression and function in rats. However, whether desensitising (low) doses of capsaicin (~ 50 mg/kg) affect tachykinin receptor and TRPV1 gene expression in the short term has yet to be investigated. The aim of the present study was to compare tachykinin receptor (NK1, NK2 and NK3) and TRPV1 mRNA expression 24 h after administration of capsaicin (50 mg/kg s.c.). Tachykinin receptor and TRPV1 mRNA were detected in all tissues studied with expression levels differing by up to 2500-fold between tissues. The highest expression of TRPV1 and NK1 mRNA was observed in the salivary gland, whereas NK2 mRNA expression was highest in the urinary bladder and NK3 mRNA expression in the frontal cortex. In the cervical spinal cord of rats treated with capsaicin, NK1 and NK3 mRNA expression were reduced by 56% and 80%, respectively (P < 0.05), whereas NK2 and TRPV1 mRNA expression were increased 2.2- and 1.4-fold, respectively (P < 0.05). NK1 and NK2 mRNA expression were decreased (P < 0.05) in the urinary bladder and gastric fundus, respectively, following capsaicin treatment. There was a marked 100-fold increase in cFOS mRNA expression and 100-fold decrease in NK2 mRNA expression in the whole blood of capsaicin-treated rats. In conclusion, these studies show that tachykinin receptor and TRPV1 mRNA expression undergo significant changes within 24 h of systemic low-dose capsaicin administration.

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Neuroscience Letters

Abstract

References (24)

Neonatal capsaicin and thermal nociception: a paradox

Brain Res.

Ureteral axon damage following subcutaneous administration of capsaicin in adult rats

Neurosci. Lett.

Selective staining of degenerating axons in the central nervous system by a simplified silver method: spinal cord projections to external cuneate and inferior olivary nuclei in the cat

Brain Res.

Capsaicin and sensory neurons

A review

Pain

Degeneration of axons in the ureteric and duodenal nerve plexuses of the adult rat following in vivo treatment with capsaicin

Neurosci. Lett.

Effect of capsaicin on the intraperitoneal axons of the rat trachea

Neurosci. Lett.

Mitochondrial alterations in the spinal ganglion cells of the rat accompanying the long-lasting sensory disturbance induced by capsaicin

Life Sci.

Regulation of substance P by nerve growth factor: disruption by capsaicin

Brain Res.

Neurotoxic action of capsaicin on spinal substance P neurons

Brain Res.

Untersuchungen über den Feinbau von Spinalganglien

Z. Zellforsch.

Decrease of substance P in primary afferent neurones and impairment of neurogenic plasma extravasation by capsaicin

Br. J. Pharmacol.

Effect of capsaicin pretreatment on capsaicinevoked release of immunoreactive somatostatin and substance P from primary sensory neurons

Naunyn-Schmiedeberg's Arch. Pharmacol.

Cited by (207)

Fight fire with fire: Neurobiology of capsaicin-induced analgesia for chronic pain

Role of capsaicin sensitive sensory nerves in ischemia reperfusion-induced acute kidney injury in rats

Sensory denervation of inguinal white fat modifies sympathetic outflow to white and brown fat in Siberian hamsters

Analysis and measurement of the sympathetic and sensory innervation of white and brown adipose tissue

Mechanism of capsaicin receptor TRPV1-mediated toxicity in pain-sensing neurons focusing on the effects of Na<sup>+</sup>/Ca<sup>2+</sup> fluxes and the Ca<sup>2+</sup>-binding protein calretinin

Tachykinin (NK1, NK2 and NK3) receptor, transient receptor potential vanilloid 1 (TRPV1) and early transcription factor, cFOS, mRNA expression in rat tissues following systemic capsaicin treatment