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Article ; Online: Dual effect of anandamide on spinal nociceptive transmission in control and inflammatory conditions.

Pontearso, Monica / Slepicka, Jakub / Bhattacharyya, Anirban / Spicarova, Diana / Palecek, Jiri

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2024 Volume 173, Page(s) 116369

Abstract: Anandamide (AEA) is an important modulator of nociception in the spinal dorsal horn, acting presynaptically through Cannabinoid ( ... ...

Abstract	Anandamide (AEA) is an important modulator of nociception in the spinal dorsal horn, acting presynaptically through Cannabinoid (CB
MeSH term(s)	Humans ; Endocannabinoids/pharmacology ; Nociception ; Polyunsaturated Alkamides/pharmacology ; Spinal Cord Dorsal Horn ; Analgesics/pharmacology ; Inflammation/drug therapy ; Amidohydrolases ; Arachidonic Acids ; Benzamides ; Carbamates
Chemical Substances	anandamide (UR5G69TJKH) ; Endocannabinoids ; cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester ; Polyunsaturated Alkamides ; Analgesics ; Amidohydrolases (EC 3.5.-) ; Arachidonic Acids ; Benzamides ; Carbamates
Language	English
Publishing date	2024-03-06
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2024.116369
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Article: Inhibition of synaptic transmission by anandamide precursor 20:4-NAPE is mediated by TRPV1 receptors under inflammatory conditions.

Spicarova, Diana / Nerandzic, Vladimir / Muzik, David / Pontearso, Monica / Bhattacharyya, Anirban / Nagy, Istvan / Palecek, Jiri

Frontiers in molecular neuroscience

2023 Volume 16, Page(s) 1188503

Abstract: Transient receptor potential ion channel, vanilloid subfamily, type 1 (TRPV1) cation channel, and cannabinoid receptor 1 ( ... ...

Abstract	Transient receptor potential ion channel, vanilloid subfamily, type 1 (TRPV1) cation channel, and cannabinoid receptor 1 (CB
Language	English
Publishing date	2023-06-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2023.1188503
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Article ; Online: Spinal PAR2 Activation Contributes to Hypersensitivity Induced by Peripheral Inflammation in Rats.

Mrozkova, Petra / Spicarova, Diana / Palecek, Jiri

International journal of molecular sciences

2021 Volume 22, Issue 3

Abstract: The mechanisms of inflammatory pain need to be identified in order to find new superior treatments. Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) are highly co-expressed in dorsal root ganglion neurons and ... ...

Abstract	The mechanisms of inflammatory pain need to be identified in order to find new superior treatments. Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) are highly co-expressed in dorsal root ganglion neurons and implicated in pain development. Here, we examined the role of spinal PAR2 in hyperalgesia and the modulation of synaptic transmission in carrageenan-induced peripheral inflammation, using intrathecal (i.t.) treatment in the behavioral experiments and recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs and eEPSCs) in spinal cord slices. Intrathecal PAR2-activating peptide (AP) administration aggravated the carrageenan-induced thermal hyperalgesia, and this was prevented by a TRPV1 antagonist (SB 366791) and staurosporine i.t. pretreatment. Additionally, the frequency of the mEPSC and sEPSC and the amplitude of the eEPSC recorded from the superficial dorsal horn neurons were enhanced after acute PAR2 AP application, while prevented with SB 366791 or staurosporine pretreatment. PAR2 antagonist application reduced the thermal hyperalgesia and decreased the frequency of mEPSC and sEPSC and the amplitude of eEPSC. Our findings highlight the contribution of spinal PAR2 activation to carrageenan-induced hyperalgesia and the importance of dorsal horn PAR2 and TRPV1 receptor interactions in the modulation of nociceptive synaptic transmission.
MeSH term(s)	Anilides/pharmacology ; Animals ; Carrageenan/pharmacology ; Carrageenan/toxicity ; Cinnamates/pharmacology ; Excitatory Postsynaptic Potentials ; Hyperalgesia/etiology ; Hyperalgesia/metabolism ; Hyperalgesia/physiopathology ; Male ; Miniature Postsynaptic Potentials ; Nociception ; Posterior Horn Cells/drug effects ; Posterior Horn Cells/metabolism ; Posterior Horn Cells/physiology ; Rats ; Rats, Wistar ; Receptor, PAR-2/metabolism ; Staurosporine/pharmacology ; TRPV Cation Channels/antagonists & inhibitors ; TRPV Cation Channels/metabolism
Chemical Substances	Anilides ; Cinnamates ; N-(3-methoxyphenyl)-4-chlorocinnamanilide ; Receptor, PAR-2 ; TRPV Cation Channels ; Trpv1 protein, rat ; Carrageenan (9000-07-1) ; Staurosporine (H88EPA0A3N)
Language	English
Publishing date	2021-01-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22030991
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Article ; Online: Hypersensitivity Induced by Intrathecal Bradykinin Administration Is Enhanced by N-oleoyldopamine (OLDA) and Prevented by TRPV1 Antagonist.

Uchytilova, Eva / Spicarova, Diana / Palecek, Jiri

International journal of molecular sciences

2021 Volume 22, Issue 7

Abstract: Transient receptor potential vanilloid 1 (TRPV1) channels contribute to the development of several chronic pain states and represent a possible therapeutic target in many painful disease treatment. Proinflammatory mediator bradykinin (BK) sensitizes ... ...

Abstract	Transient receptor potential vanilloid 1 (TRPV1) channels contribute to the development of several chronic pain states and represent a possible therapeutic target in many painful disease treatment. Proinflammatory mediator bradykinin (BK) sensitizes TRPV1, whereas noxious peripheral stimulation increases BK level in the spinal cord. Here, we investigated the involvement of spinal TRPV1 in thermal and mechanical hypersensitivity, evoked by intrathecal (i.t.) administration of BK and an endogenous agonist of TRPV1, N-oleoyldopamine (OLDA), using behavioral tests and i.t. catheter implantation, and administration of BK-induced transient thermal and mechanical hyperalgesia and mechanical allodynia. All these hypersensitive states were enhanced by co-administration of a low dose of OLDA (0.42 µg i.t.), which was ineffective only under the control conditions. Intrathecal pretreatment with TRPV1 selective antagonist SB366791 prevented hypersensitivity induced by i.t. co-administration of BK and OLDA. Our results demonstrate that both thermal and mechanical hypersensitivity evoked by co-administration of BK and OLDA is mediated by the activation of spinal TRPV1 channels.
MeSH term(s)	Animals ; Bradykinin ; Dopamine/analogs & derivatives ; Hyperalgesia/metabolism ; Injections, Spinal ; Male ; Rats, Wistar ; Spinal Cord/metabolism ; TRPV Cation Channels/agonists ; TRPV Cation Channels/metabolism ; Rats
Chemical Substances	TRPV Cation Channels ; TRPV1 protein, mouse ; Bradykinin (S8TIM42R2W) ; N-oleoyldopamine (T87P7X9XSZ) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2021-04-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22073712
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Article ; Online: Chemokine CCL2 prevents opioid-induced inhibition of nociceptive synaptic transmission in spinal cord dorsal horn.

Heles, Mario / Mrozkova, Petra / Sulcova, Dominika / Adamek, Pavel / Spicarova, Diana / Palecek, Jiri

Journal of neuroinflammation

2021 Volume 18, Issue 1, Page(s) 279

Abstract: ... slices superficial dorsal horn neurons were used to evaluate the effect of µOR agonist [D-Ala: Results ...

Abstract	Background: Opioid analgesics remain widely used for pain treatment despite the related serious side effects. Some of those, such as opioid tolerance and opioid-induced hyperalgesia may be at least partially due to modulation of opioid receptors (OR) function at nociceptive synapses in the spinal cord dorsal horn. It was suggested that increased release of different chemokines under pathological conditions may play a role in this process. The goal of this study was to investigate the crosstalk between the µOR, transient receptor potential vanilloid 1 (TRPV1) receptor and C-C motif ligand 2 (CCL2) chemokine and the involvement of spinal microglia in the modulation of opioid analgesia. Methods: Patch-clamp recordings of miniature excitatory postsynaptic currents (mEPSCs) and dorsal root evoked currents (eEPSC) in spinal cord slices superficial dorsal horn neurons were used to evaluate the effect of µOR agonist [D-Ala Results: Application of DAMGO induced a rapid decrease of mEPSC frequency and eEPSC amplitude, followed by a delayed increase of the eESPC amplitude, which was prevented by SB366791. Chemokine CCL2 treatment significantly diminished all the DAMGO-induced changes. Minocycline treatment prevented the CCL2 effects on the DAMGO-induced eEPSC depression, while mEPSC changes were unaffected. In behavioral experiments, i.t. injection of CCL2 completely blocked DAMGO-induced thermal hypoalgesia and intraperitoneal pre-treatment with minocycline prevented the CCL2 effect. Conclusions: Our results indicate that opioid-induced inhibition of the excitatory synaptic transmission could be severely attenuated by increased CCL2 levels most likely through a microglia activation-dependent mechanism. Delayed potentiation of neurotransmission after µOR activation is dependent on TRPV1 receptors activation. Targeting CCL2 and its receptors and TRPV1 receptors in combination with opioid therapy could significantly improve the analgesic properties of opioids, especially during pathological states.
MeSH term(s)	Analgesics, Opioid/pharmacology ; Anilides/pharmacology ; Animals ; Chemokine CCL2/pharmacology ; Cinnamates/pharmacology ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology ; Excitatory Postsynaptic Potentials/drug effects ; Male ; Miniature Postsynaptic Potentials/drug effects ; Neurons/drug effects ; Nociception/drug effects ; Rats ; Rats, Wistar ; Spinal Cord/drug effects ; Spinal Cord Dorsal Horn/drug effects ; Synaptic Transmission/drug effects
Chemical Substances	Analgesics, Opioid ; Anilides ; Chemokine CCL2 ; Cinnamates ; N-(3-methoxyphenyl)-4-chlorocinnamanilide ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)- (100929-53-1)
Language	English
Publishing date	2021-12-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-021-02335-4
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Article: The role of spinal cord vanilloid (TRPV1) receptors in pain modulation.

Spicarová, D / Palecek, J

Physiological research

2008 Volume 57 Suppl 3, Page(s) S69–S77

Abstract: Transient receptor potential vanilloid 1 (TRPV1) receptor is a nonselective cation channel activated by capsaicin, a pungent substance from chili peppers. It is considered to act as an integrator of various physical and chemical nociceptive stimuli, as ... ...

Abstract	Transient receptor potential vanilloid 1 (TRPV1) receptor is a nonselective cation channel activated by capsaicin, a pungent substance from chili peppers. It is considered to act as an integrator of various physical and chemical nociceptive stimuli, as it can be gated by noxious heat (>43 oC), low pH (protons) and also by recently described endogenous lipids. The structure and function of TRPV1 receptors was vigorously studied, especially since its cloning in 1997. However, most of the research was pointed towards the role of TRPV1 receptors in the peripheral tissues. Mounting evidence now suggests that TRPV1 receptors on the central branches of dorsal root ganglion neurons in the spinal cord may play an important role in modulation of pain and nociceptive transmission. The aim of this short review was to summarize the knowledge about TRPV1 receptors in the spinal cord dorsal horn, preferentially from morphological and electrophysiological studies on spinal cord slices and from in vivo experiments.
MeSH term(s)	Animals ; Capsaicin/pharmacology ; Ganglia, Spinal/metabolism ; Humans ; Pain/physiopathology ; Spinal Cord/metabolism ; Synaptic Transmission/physiology ; TRPV Cation Channels/metabolism
Chemical Substances	TRPV Cation Channels ; TRPV1 receptor ; Capsaicin (S07O44R1ZM)
Language	English
Publishing date	2008-05-13
Publishing country	Czech Republic
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1073141-6
ISSN	1802-9973 ; 0862-8408 ; 0369-9463
ISSN (online)	1802-9973
ISSN	0862-8408 ; 0369-9463
DOI	10.33549/physiolres.931601
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Zs.A 228: Show issues

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Article ; Online: The role of protease-activated receptor type 2 in nociceptive signaling and pain.

Mrozkova, P / Palecek, J / Spicarova, D

Physiological research

2016 Volume 65, Issue 3, Page(s) 357–367

Abstract: Protease-activated receptors (PARs) belong to the G-protein-coupled receptor family, that are expressed in many body tissues especially in different epithelial cells, mast cells and also in neurons and astrocytes. PARs play different physiological roles ... ...

Abstract	Protease-activated receptors (PARs) belong to the G-protein-coupled receptor family, that are expressed in many body tissues especially in different epithelial cells, mast cells and also in neurons and astrocytes. PARs play different physiological roles according to the location of their expression. Increased evidence supports the importance of PARs activation during nociceptive signaling and in the development of chronic pain states. This short review focuses on the role of PAR2 receptors in nociceptive transmission with the emphasis on the modulation at the spinal cord level. PAR2 are cleaved and subsequently activated by endogenous proteases such as tryptase and trypsin. In vivo, peripheral and intrathecal administration of PAR2 agonists induces thermal and mechanical hypersensitivity that is thought to be mediated by PAR2-induced release of pronociceptive neuropeptides and modulation of different receptors. PAR2 activation leads also to sensitization of transient receptor potential channels (TRP) that are crucial for nociceptive signaling and modulation. PAR2 receptors may play an important modulatory role in the development and maintenance of different pathological pain states and could represent a potential target for new analgesic treatments.
MeSH term(s)	Animals ; Cancer Pain/metabolism ; Humans ; Neuralgia/metabolism ; Nociception ; Nociceptive Pain/metabolism ; Protein Kinases/metabolism ; Receptor, PAR-2/metabolism ; Signal Transduction ; Spinal Cord/metabolism ; Transient Receptor Potential Channels/metabolism
Chemical Substances	Receptor, PAR-2 ; Transient Receptor Potential Channels ; Protein Kinases (EC 2.7.-)
Language	English
Publishing date	2016-04-12
Publishing country	Czech Republic
Document type	Journal Article ; Review
ZDB-ID	1073141-6
ISSN	1802-9973 ; 0369-9463 ; 0862-8408
ISSN (online)	1802-9973
ISSN	0369-9463 ; 0862-8408
DOI	10.33549/physiolres.933269
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Article ; Online: Hypersensitivity Induced by Activation of Spinal Cord PAR2 Receptors Is Partially Mediated by TRPV1 Receptors.

Mrozkova, Petra / Spicarova, Diana / Palecek, Jiri

PloS one

2016 Volume 11, Issue 10, Page(s) e0163991

Abstract: Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) receptors in the peripheral nerve endings are implicated in the development of increased sensitivity to mechanical and thermal stimuli, especially during ... ...

Abstract	Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) receptors in the peripheral nerve endings are implicated in the development of increased sensitivity to mechanical and thermal stimuli, especially during inflammatory states. Both PAR2 and TRPV1 receptors are co-expressed in nociceptive dorsal root ganglion (DRG) neurons on their peripheral endings and also on presynaptic endings in the spinal cord dorsal horn. However, the modulation of nociceptive synaptic transmission in the superficial dorsal horn after activation of PAR2 and their functional coupling with TRPV1 is not clear. To investigate the role of spinal PAR2 activation on nociceptive modulation, intrathecal drug application was used in behavioural experiments and patch-clamp recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs, eEPSCs) were performed on superficial dorsal horn neurons in acute rat spinal cord slices. Intrathecal application of PAR2 activating peptide SLIGKV-NH2 induced thermal hyperalgesia, which was prevented by pretreatment with TRPV1 antagonist SB 366791 and was reduced by protein kinases inhibitor staurosporine. Patch-clamp experiments revealed robust decrease of mEPSC frequency (62.8 ± 4.9%), increase of sEPSC frequency (127.0 ± 5.9%) and eEPSC amplitude (126.9 ± 12.0%) in dorsal horn neurons after acute SLIGKV-NH2 application. All these EPSC changes, induced by PAR2 activation, were prevented by SB 366791 and staurosporine pretreatment. Our results demonstrate an important role of spinal PAR2 receptors in modulation of nociceptive transmission in the spinal cord dorsal horn at least partially mediated by activation of presynaptic TRPV1 receptors. The functional coupling between the PAR2 and TRPV1 receptors on the central branches of DRG neurons may be important especially during different pathological states when it may enhance pain perception.
MeSH term(s)	Anilides/pharmacology ; Animals ; Behavior, Animal/drug effects ; Cinnamates/pharmacology ; Excitatory Postsynaptic Potentials/drug effects ; Hyperalgesia/etiology ; Hyperalgesia/prevention & control ; Hypersensitivity/metabolism ; Hypersensitivity/pathology ; In Vitro Techniques ; Male ; Oligopeptides/pharmacology ; Patch-Clamp Techniques ; Posterior Horn Cells/drug effects ; Posterior Horn Cells/physiology ; Protein Kinase Inhibitors/pharmacology ; Rats ; Rats, Wistar ; Receptor, PAR-2/agonists ; Receptor, PAR-2/metabolism ; Spinal Cord/metabolism ; Staurosporine/pharmacology ; Synaptic Transmission/physiology ; TRPV Cation Channels/antagonists & inhibitors ; TRPV Cation Channels/metabolism
Chemical Substances	Anilides ; Cinnamates ; N-(3-methoxyphenyl)-4-chlorocinnamanilide ; Oligopeptides ; Protein Kinase Inhibitors ; Receptor, PAR-2 ; TRPV Cation Channels ; TRPV1 receptor ; seryl-leucyl-isoleucyl-glycyl-lysyl-valinamide ; Staurosporine (H88EPA0A3N)
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0163991
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Article ; Online: Single high-concentration capsaicin application prevents c-Fos expression in spinothalamic and postsynaptic dorsal column neurons after surgical incision.

Uchytilova, E / Spicarova, D / Palecek, J

European journal of pain (London, England)

2015 Volume 19, Issue 10, Page(s) 1496–1505

Abstract: Background: Allodynia and hyperalgesia present after surgical interventions are often a major complain of surgical patients. It is thought that both peripheral and central mechanisms contribute to these symptoms. In this study, the role of peripheral ... ...

Abstract	Background: Allodynia and hyperalgesia present after surgical interventions are often a major complain of surgical patients. It is thought that both peripheral and central mechanisms contribute to these symptoms. In this study, the role of peripheral nerve fibres that express transient receptor potential vanilloid 1 (TRPV1) receptors in the activation of spinothalamic tract (STT) and postsynaptic dorsal column (PSDC) neurons was assessed in a model of surgical pain. Methods: Spinothalamic tract and PSDC neurons retrogradely labelled from the thalamus and nucleus gracilis were used. Activation of these projection neurons was evaluated after plantar incision as expression of the early gene product, c-Fos protein, in the nuclei of these neurons. Results: There was a robust increase in c-Fos immunopositivity in the STT and PSDC neurons, in the control animals after a plantar incision. This increase in c-Fos expression was significantly attenuated in animals in which a single high-concentration capsaicin injection was made intradermally at the incision site 24 h before the surgery. Conclusions: Our results suggest that activation of both STT and PSDC neurons is involved in development of pain states present after surgical incision and that TRPV1-containing peripheral nerve fibres are needed for c-Fos expression in these dorsal horn neurons after plantar incision.
MeSH term(s)	Animals ; Capsaicin/administration & dosage ; Capsaicin/pharmacology ; Disease Models, Animal ; Male ; Medulla Oblongata/metabolism ; Nerve Fibers/drug effects ; Nerve Fibers/metabolism ; Pain, Postoperative/drug therapy ; Pain, Postoperative/etiology ; Pain, Postoperative/metabolism ; Posterior Horn Cells/metabolism ; Proto-Oncogene Proteins c-fos/drug effects ; Proto-Oncogene Proteins c-fos/metabolism ; Rats ; Rats, Wistar ; Sensory System Agents/administration & dosage ; Sensory System Agents/pharmacology ; Spinothalamic Tracts/drug effects ; Spinothalamic Tracts/metabolism ; TRPV Cation Channels/metabolism
Chemical Substances	Proto-Oncogene Proteins c-fos ; Sensory System Agents ; TRPV Cation Channels ; Trpv1 protein, rat ; Capsaicin (S07O44R1ZM)
Language	English
Publishing date	2015-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1390424-3
ISSN	1532-2149 ; 1090-3801
ISSN (online)	1532-2149
ISSN	1090-3801
DOI	10.1002/ejp.683
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Article ; Online: Update on the role of spinal cord TRPV1 receptors in pain modulation.

Spicarova, D / Nerandzic, V / Palecek, J

Physiological research

2014 Volume 63, Issue Suppl 1, Page(s) S225–36

Abstract: ... This short review is a follow up on our previous summary in this area (Spicarova and Palecek 2008). The aim ...

Abstract	The structure, expression and function of the transient receptor potential vanilloid 1 (TRPV1) receptor were intensively studied since the cloning in 1997 and TRPV1 receptors are now considered to act as transducers and molecular integrators of nociceptive stimuli in the periphery. In contrast, spinal TRPV1 receptors were studied less extensively and their role in pain modulation is still not fully understood. This short review is a follow up on our previous summary in this area (Spicarova and Palecek 2008). The aim was to review preferentially the most recent findings concerning the role of the spinal TRPV1 receptors, published within the last five years. The update is given on the expression and function of the spinal TRPV1 receptors, their activation by endogenous agonists, interaction between the endocannabinoid and endovanillod system and possible role of the spinal TRPV1 receptors in pathological pain states. There is now mounting evidence that TRPV1 receptors may be an important element in modulation of nociceptive information at the spinal cord level and represent an interesting target for analgesic therapy.
MeSH term(s)	Animals ; Endocannabinoids/metabolism ; Humans ; Pain/physiopathology ; Pain Perception ; Spinal Cord/physiopathology ; TRPV Cation Channels/metabolism
Chemical Substances	Endocannabinoids ; TRPV Cation Channels ; TRPV1 receptor
Language	English
Publishing date	2014-02-04
Publishing country	Czech Republic
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1073141-6
ISSN	1802-9973 ; 0369-9463 ; 0862-8408
ISSN (online)	1802-9973
ISSN	0369-9463 ; 0862-8408
DOI	10.33549/physiolres.932713
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