The role of calcium in capsaicin-induced desensitization in rat cultured dorsal root ganglion neurons

doi:10.1016/0306-4522(93)90315-7

Neuroscience

Volume 55, Issue 4, August 1993, Pages 1015-1023

https://doi.org/10.1016/0306-4522(93)90315-7 Get rights and content

Abstract

The effects of capsaicin cytosolic Ca²⁺ concentration ([Ca²⁺]_i) were measured in individual dorsal root ganglion neurons of the rat in culture. Capsaicin produced a rapid concentration-dependent (EC₅₀ value of 72 nM) Increase in [Ca²⁺]_i, which was entirely dependent on Ca²⁺ entry. Exposure of the neurons to a high concentration of capsaicin resulted in desensitization, but only in the presence of external Ca²⁺. Raising [Ca²⁺]_i with a depolarizing concentration of potassium or the Ca²⁺ ionophore ionomycin did not reduce the response to a subsequent application of capsaicin. Capsaicin did not induce desensitization in Ca²⁺-free medium even if [Ca²⁺]_i, was simultaneously raised with a combination of ionomycin plus carbonyl cyanide m-chlorophenyl-hydrazone. Okadaic acid, a known inhibitor of protein phosphatases 1 and 2A, caused a transient dose-dependent (EC₅₀ value, 100 nM) rise in [Ca²⁺]_i, but had no effect on either the responsiveness to capsaicin or capsaicin induced desensitization. The capsaicin antagonist capsazepine blocked the increase in [Ca²⁺]_i evoked by capsaicin and prevented desensitization.

These results suggest that desensitization requires the presence of extracellular Ca²⁺, cannot be mimicked by raising the concentration of [Ca²⁺]_i and may involve Ca²⁺ entry through activated capsaicin-operated ion channels.

Reference (37)

AmannR. et al.
Capsaicin-induced Stimulation of polymodal nociceptors is antagonized by Ruthenium Red independently of extracellular calcium
Neuroscience
(1989)
CohenP. et al.
Okadaic acid: a new probe for the study of cellular regulation
Trends Biochem. Sci.
(1990)
DochertyR.J. et al.
Prolonged inhibition of voltage-dependent calcium currents induced by capsaicin in adult rat dorsal root ganglion neurons in culture
Neuroscience
(1991)
DrayA. et al.
Desensitization and capsaicin-induced release of substance P-like immunoreactivity from guinea-pig ureter in vitro
Neuroscience
(1989)
DrayA. et al.
Ruthenium Red blocks the capsaicin-induced increase in intracellular calcium and activation of membrane currents in sensory neurones as well as the activation of peripheral nociceptors in vitro
Neurosci. Lett
(1990)
FitzgeraldM.
Capsaicin and sensory neurones—a review
Pain
(1983)
GrynkiewiczG. et al.
A new generation of Ca²⁺ indicators with greatly improved fluorescence properties
J. biol. Chem.
(1985)
HeymanI. et al.
Depolarizing responses to capsaicin in a subpopulation of rat dorsal root ganglion cells
Neurosci. Lett.
(1985)
HolzerP.
Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides
Neuroscience
(1988)
LynnB.
Capsaicin: actions on nociceptive C-fibres and therapeutic potential
Pain
(1990)

MaggiC.A. et al.

The sensory-efferent function of capsaicin-sensitive sensory neurons

Gen. Pharmac.

(1988)

MaggiC.A. et al.

Protective action of Ruthenium Red toward capsaicin desensitization of sensory fibres

Neurosci. Lett.

(1988)

MaggiC.A. et al.

The antagonism induced by Ruthenium Red of the actions of capsaicin on the peripheral terminals of sensory neurons: further studies

Eur. J. Pharmac.

(1988)

MarshS.J. et al.

The mechanism of action of capsaicin on sensory C-type neurons and their axons in vitro

Neuroscience

(1987)

QuZ.C. et al.

Regulation of tyrosine phosphorylation of the nicotonic acetylcholine receptor at the rat neuromuscular junction

Neuron

(1990)

SanticioliP. et al.

Exposure to calcium-free medium protects sensory fibres by capsaicin desensitization

Neurosci. Lett.

(1987)

BaranowskiR. et al.

The effects of locally applied capsaicin on conduction in cutaneous nerves in four mammalian special

Br. J. Pharmac.

(1986)

BevanS. et al.

Membrane effects of capsaicin on rat dorsal root ganglion neurones in cell culture

J. Physiol.

(1988)

Cited by (130)

3.20 - Oral Chemesthesis and Taste
2020, The Senses: A Comprehensive Reference: Volume 1-7, Second Edition
Chemesthesis is defined as the sensitivity of mucosal surfaces to environmental chemicals. Activation of this system elicits thermal, nociceptive, and tactile sensations. In the oral cavity, mucosal surfaces respond to compounds found commonly in foods and the evoked sensations contribute to the overall flavor percept. Presently, the transduction and coding mechanisms underpinning many of the psychophysical observations made in humans are described. Similarly, interactions between oral chemesthesis and taste pathways have been investigated. These events occur both peripherally and centrally and provide the basis for the reciprocal modulatory activity observed perceptually between these systems.
TRPV currents and their role in the nociception and neuroplasticity
2016, Neuropeptides
Transient receptor potential channels sensitive to vanilloids (TRPVs) are group of ion channels which are sensitive to various tissue damaging signals and their activation is generally perceived as pain. Therefore, they are generally named as nociceptors. Understanding their activation and function as well as their interaction with intracellular pathways is crucial for the development of pharmacological interference in order to reduce pain perception. The current review summarizes basic facts in regard to TRPV and discusses their relevance in the sensing of (pain-) signals and their intracellular processing, focussing on their modulation of the intracellular calcium ([Ca^2 +]_i) signal. Furthermore we discuss the basic mechanisms how the modification of [Ca^2 +]_i through TRPV might induce long-term-potentiation (LTP) or long-term- depression (LTD) and from “memories” of pain. Understanding of these mechanisms is needed to localize the best point of interference for pharmacological treatment. Therefore, high attention is given to highlight physiological and pathological processes and their interaction with significant modulators and their roles in neuroplasticity and pain modulation.
P2X<inf>3</inf> and TRPV1 functionally interact and mediate sensitization of trigeminal sensory neurons
2013, Neuroscience
Musculoskeletal pain conditions, particularly those associated with temporomandibular disorders (TMD) affect a large percentage of the population. Identifying mechanisms underlying hyperalgesia could contribute to the development of new treatment strategies for the management of TMD and other muscle pain conditions. In this study, we provide evidence of functional interactions between two ligand-gated channels, P2X₃ and transient receptor potential V1 (TRPV1), in trigeminal sensory neurons, and propose that the interactions serve as an underlying mechanism for the development of mechanical hyperalgesia. Mechanical sensitivity of the masseter muscle was assessed in lightly anesthetized rats via an electronic anesthesiometer (Ro et al., 2009). Direct intramuscular injection of a selective P2X₃ agonist, alpha,beta-methylene adenosine triphosphate (αβmeATP), induced a dose- and time-dependent hyperalgesia. Mechanical sensitivity in the contralateral muscle was unaffected suggesting local P2X₃ mediate hyperalgesia. Anesthetizing the overlying skin had no effect on αβmeATP-induced hyperalgesia confirming the contribution of P2X₃ from the muscle. Importantly, the αβmeATP-induced hyperalgesia was prevented by pretreatment of the muscle with a TRPV1 antagonist, AMG9810. P2X₃ was co-expressed with TRPV1 in the masseter muscle afferents confirming the possibility for intracellular interactions. Additionally, in a subpopulation of P2X₃/TRPV1 positive neurons, capsaicin-induced Ca²⁺ transients were significantly amplified following P2X₃ activation. Finally, activation of P2X₃ induced phosphorylation of serine, but not threonine, residues in TRPV1 in trigeminal ganglia cultures. Significant phosphorylation was observed at 15 min, the time point at which behavioral hyperalgesia was prominent. Previously, activation of either P2X₃ or TRPV1 had been independently implicated in the development of mechanical hyperalgesia. Our data propose P2X₃ and TRPV1 interact in a facilitatory manner, which could contribute to the peripheral sensitization known to underlie masseter hyperalgesia.
N-glycosylation determines ionic permeability and desensitization of the TRPV1 capsaicin receptor
2012, Journal of Biological Chemistry
The balance of glycosylation and deglycosylation of ion channels can markedly influence their function and regulation. However, the functional importance of glycosylation of the TRPV1 receptor, a key sensor of pain-sensing nerves, is not well understood, and whether TRPV1 is glycosylated in neurons is unclear. We report that TRPV1 is N-glycosylated and that N-glycosylation is a major determinant of capsaicin-evoked desensitization and ionic permeability. Both N-glycosylated and unglycosylated TRPV1 was detected in extracts of peripheral sensory nerves by Western blotting. TRPV1 expressed in HEK-293 cells exhibited various degrees of glycosylation. A mutant of asparagine 604 (N604T) was not glycosylated but did not alter plasma membrane expression of TRPV1. Capsaicin-evoked increases in intracellular calcium ([Ca²⁺]_i) were sustained in wild-type TRPV1 HEK-293 cells but were rapidly desensitized in N604T TRPV1 cells. There was marked cell-to-cell variability in capsaicin responses and desensitization between individual cells expressing wild-type TRPV1 but highly uniform responses in cells expressing N604T TRPV1, consistent with variable levels of glycosylation of the wild-type channel. These differences were also apparent when wild-type or N604T TRPV1-GFP fusion proteins were expressed in neurons from trpv1^−/− mice. Capsaicin evoked a marked, concentration-dependent increase in uptake of the large cationic dye YO-PRO-1 in cells expressing wild-type TRPV1, indicative of loss of ion selectivity, that was completely absent in cells expressing N604T TRPV1. Thus, TRPV1 is variably N-glycosylated and glycosylation is a key determinant of capsaicin regulation of TRPV1 desensitization and permeability. Our findings suggest that physiological or pathological alterations in TRPV1 glycosylation would affect TRPV1 function and pain transmission.
Nociceptive sensitization by complement C5a and C3a in mouse
2010, Pain
Citation Excerpt :
TRPV1-mediated responses were elicited by two consecutive capsaicin applications (50 nM, 10 s). Under the control conditions (no additional treatment), the amplitude of the second [Ca2+]i response was markedly smaller than that of the first one, likely as a result of Ca2+/calcineurin-dependent desensitization of TRPV1 [2,23], yielding the response ratio of 0.14 ± 0.03 (n = 19; Fig. 7d). Treatments with either C5a or C3a between the capsaicin applications strongly potentiated the second capsaicin-induced [Ca2+]i response (Fig. 7e and f).
Activation of the complement system by injury increases inflammation by producing complement fragments C5a and C3a which are able to recruit and activate immune cells. Complement activation may contribute to pain after inflammation and injury. In this study, we examined whether C5a and C3a elicit nociception when injected into mouse hind paws in vivo, and whether C5a and C3a activate and/or sensitize mechanosensitive nociceptors when applied on peripheral terminals in vitro. We also examined the dorsal root ganglia (DRG) for C5a receptor (C5aR) mRNA and effects of C5a and C3a on intracellular Ca²⁺ concentration ([Ca²⁺]_i) using Ca²⁺ imaging. Heat hyperalgesia was elicited by intraplantar injection of C5a, and mechanical hyperalgesia by C5a and C3a. After exposure to either C5a or C3a, C-nociceptors were sensitized to heat as evidenced by an increased proportion of heat responsive fibers, lowered response threshold to heat and increased action potentials during and after heat stimulation. A-nociceptors were activated by complement. However, no change was observed in mechanical responses of A- and C-nociceptors after C5a and C3a application. The presence of C5aR mRNA was detected in DRG. C5a and C3a application elevated [Ca²⁺]_i and facilitated capsaicin-induced [Ca²⁺]_i responses in DRG neurons. The results suggest a potential role for complement fragments C5a and C3a in nociception by activating and sensitizing cutaneous nociceptors.
Bortezomib-induced neuropathy is in part mediated by the sensitization of TRPV1 channels
2023, Communications Biology

View all citing articles on Scopus

View full text

The role of calcium in capsaicin-induced desensitization in rat cultured dorsal root ganglion neurons

Abstract

Neuroscience

Trends Biochem. Sci.

Neuroscience

Neuroscience

Neurosci. Lett

Pain

J. biol. Chem.

Neurosci. Lett.

Neuroscience

Pain

Gen. Pharmac.

Neurosci. Lett.

Eur. J. Pharmac.

Neuroscience

Neuron

Neurosci. Lett.

The effects of locally applied capsaicin on conduction in cutaneous nerves in four mammalian special

Br. J. Pharmac.

Membrane effects of capsaicin on rat dorsal root ganglion neurones in cell culture

J. Physiol.