Behavioral evidence of thermal hyperalgesia and mechanical allodynia induced by intradermal cinnamaldehyde in rats

Tsagareli, Merab G.; Tsiklauri, Nana; Zanotto, Karen L.; Carstens, Mirela Iodi; Klein, Amanda H.; Sawyer, Carolyn M.; Gurtskaia, Gulnazi; Abzianidze, Elene; Carstens, Earl

doi:10.1016/j.neulet.2010.02.056

Cited by 43 publications

(35 citation statements)

References 30 publications

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“…These discrepancies regarding the effects of CA on cold pain perception and neuronal responses may partly involve the route of delivery and accessibility of CA to intradermal nociceptors. In our preliminary investigation [58] and in the present study, intradermal injection of CA allowed for a direct access to nociceptive nerve endings, resulting in significant cold hyperalgesia and enhancement of cold avoidance.…”

Section: Discussionsupporting

confidence: 50%

Behavioral Testing of the Effects of Thermosensitive TRP Channel Agonists on Touch, Temperature, and Pain Sensations

Tsagareli¹

2011

Neurophysiology

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It was recently found that transient receptor potential (TRP) channels play an important role in the transduction of thermal, mechanical, and chemical stimuli underlying the somatic sensation. Several types of TRP channels exhibit sensitivity to increases or decreases in temperature, as well as to the action of chemical ligands that elicit similar thermal or painful sensations. These agents include menthol, mustard oil, cinnamaldehyde (CA), gingerol, capsaicin, camphor, eugenol, and others. Cinnamaldehyde is a pungent chemical obtained from cinnamon, which acts as an agonist of the TRPA1 channels; these channels were originally reported to be activated by cold temperatures (below 18°C). TRPA1 is also implicated in cold nociception. However, its role in the formation of cold pain is more controversial, with discrepant reports that TRPA1s do or do not respond to intense cooling. Menthol derived from plants of the mint family enhances the feeling of coldness by interacting with the cold-sensitive TRPM8 channels, but its effect on pain is less well understood. Using behavioral methods, we showed that unilateral intraplantar injection of CA (5 to 20%) induced a significant concentration-dependent decrease in the latency for ipsilateral paw withdrawal from a noxious heat stimulus, i.e., heat hyperalgesia. Cinnamaldehyde also significantly reduced mechanical withdrawal thresholds for the injected paw, i.e., evoked mechanical allodynia. Bilateral intraplantar injections of CA resulted in a significant cold hyperalgesia (cold plate test) and a weak enhancement of innocuous cold avoidance (thermal preference test). In contrast to CA, menthol in a dose-dependent manner increased the latency for noxious heat-evoked withdrawal, i.e., exerted an antinociceptive effect. Menthol did not affect mechanosensation except for a weak allodynic effect when applied in the highest concentration used (40 %), indicating that it did not exert a local anesthetic effect. Menthol had a biphasic effect on cold avoidance. High concentrations of menthol reduced cold avoidance, i.e., induced cold hypoalgesia, while low menthol concentrations significantly intensified cold avoidance. The highest menthol concentration provided cold hypoalgesia (cold plate test), while lower concentrations had no effect. Taken together, our data support the idea that TRPA1 and TRPM8 channels represent promising peripheral targets for pain modulation.

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Section: Discussionsupporting

confidence: 50%

Behavioral Testing of the Effects of Thermosensitive TRP Channel Agonists on Touch, Temperature, and Pain Sensations

Tsagareli¹

2011

Neurophysiology

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“…Furthermore, several groups have shown that during inflammation, spinal TRPV1 receptors contribute significantly to both tactile allodynia and thermal hyperalgesia, but TRPV1 on peripheral terminals preferentially mediates the latter (7,(37)(38)(39). Peripheral activation of TRPA1 produces some thermal hyperalgesia, but the resulting tactile allodynia is the more robust response (40). Thus, the current work demonstrates that spinal HXA 3 contributes to the development of inflammatory hyperalgesia, preferentially initiating tactile allodynia via activation of TRPV1 and TRPA1 on central terminals.…”

Section: Discussionmentioning

confidence: 52%

Spinal 12-lipoxygenase-derived hepoxilin A₃contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors

Gregus¹,

Doolen

Dumlao

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

106

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Peripheral inflammation initiates changes in spinal nociceptive processing leading to hyperalgesia. Previously, we demonstrated that among 102 lipid species detected by LC-MS/MS analysis in rat spinal cord, the most notable increases that occur after intraplantar carrageenan are metabolites of 12-lipoxygenases (12-LOX), particularly hepoxilins (HXA 3 and HXB 3 ). Thus, we examined involvement of spinal LOX enzymes in inflammatory hyperalgesia. In the current work, we found that intrathecal (IT) delivery of the LOX inhibitor nordihydroguaiaretic acid prevented the carrageenan-evoked increase in spinal HXB 3 at doses that attenuated the associated hyperalgesia. Furthermore, IT delivery of inhibitors targeting 12-LOX (CDC, Baicalein), but not 5-LOX (Zileuton) dosedependently attenuated tactile allodynia. Similarly, IT delivery of 12-LOX metabolites of arachidonic acid 12(S)-HpETE, 12(S)-HETE, HXA 3 , or HXB 3 evoked profound, persistent tactile allodynia, but 12(S)-HpETE and HXA 3 produced relatively modest, transient heat hyperalgesia. The pronociceptive effect of HXA 3 correlated with enhanced release of Substance P from primary sensory afferents. Importantly, HXA 3 triggered sustained mobilization of calcium in cells stably overexpressing TRPV1 or TRPA1 receptors and in acutely dissociated rodent sensory neurons. Constitutive deletion or antagonists of TRPV1 (AMG9810) or TRPA1 (HC030031) attenuated this action. Furthermore, pretreatment with antihyperalgesic doses of AMG9810 or HC030031 reduced spinal HXA 3 -evoked allodynia. These data indicate that spinal HXA 3 is increased by peripheral inflammation and promotes initiation of facilitated nociceptive processing through direct activation of TRPV1 and TRPA1 at central terminals.eicosanoid | pain | central sensitization T issue injury and inflammation are associated with hyperalgesia mediated by facilitated spinal nociceptive processing that can be modulated by lipids derived from arachidonic acid (AA) and other polyunsaturated fatty acids (PUFA), including eicosanoids synthesized via three enzymatic pathways: (i) cyclooxygenase (COX)-prostaglandins (PG); (ii) 5-, 12-, and 12/15-lipoxygenases (LOX)-leukotrienes, hydroxyeicosatetraenoic acids (HETEs), hepoxilins (HXA 3 and HXB 3 ), lipoxins, resolvins, and protectins; and (iii) cytochrome P450-epoxyeicosatrienoic acids and HETEs (1). Substantial evidence indicates that peripheral injury or direct activation of spinal dorsal horn receptors [Neurokinin 1 (NK1), AMPA, and NMDA] increases eicosanoid formation and that spinal delivery of COX inhibitors reduces the associated hyperalgesia (2, 3). Recently, we reported that paw carrageenan increases spinal production of both COX and 12-LOX metabolites of AA, including 12(S)-HETE in cerebrospinal fluid (CSF) and hepoxilins in the lumbar spinal cord (4).Several groups point to a peripheral role for 5-and 12-LOX in nociception, as shown by antihyperalgesic actions of LOX inhibitors administered via systemic routes (5-9). It has been suggested that spinal 12-LOX may play a r...

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“…However, increasing data connect TRPA1 to heat sensitivity. In particular, TRPA1 agonists induce heat and mechanical hyperalgesia and a burning pain sensation, but no cold hyperalgesia (Namer et al, 2005;Albin et al, 2008;Merrill et al, 2008;Zanotto et al, 2008;Sawyer et al, 2009;Carstens et al, 2010;Tsagareli et al, 2010;Tsagareli, 2011Tsagareli, , 2013Hoffmann et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Role of thermo TRPA1 and TRPV1 channels in heat, cold, and mechanical nociception of rats

Nozadze¹,

Tsiklauri²,

Gurtskaia³

et al. 2016

Behavioural Pharmacology

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A sensitive response of the nervous system to changes in temperature is of predominant importance for homeotherms to maintain a stable body temperature. A number of temperature-sensitive transient receptor potential (TRP) ion channels have been studied as nociceptors that respond to extreme temperatures and harmful chemicals. Recent findings in the field of pain have established a family of six thermo-TRP channels (TRPA1, TRPM8, TRPV1, TRPV2, TRPV3, and TRPV4) that exhibit sensitivity to increases or decreases in temperature, as well as to chemical substances eliciting the respective hot or cold sensations. In this study, we used behavioral methods to investigate whether mustard oil (allyl isothiocyanate) and capsaicin affect the sensitivity to heat, innocuous and noxious cold, and mechanical stimuli in male rats. The results obtained indicate that TRPA1 and TRPV1 channels are clearly involved in pain reactions, and the TRPA1 agonist allyl isothiocyanate enhances the heat pain sensitivity, possibly by indirectly modulating TRPV1 channels coexpressed in nociceptors with TRPA1. Overall, our data support the role of thermosensitive TRPA1 and TRPV1 channels in pain modulation and show that these two thermoreceptor channels are in a synergistic and/or conditional relationship with noxious heat and cold cutaneous stimulation.

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Behavioral evidence of thermal hyperalgesia and mechanical allodynia induced by intradermal cinnamaldehyde in rats

Cited by 43 publications

References 30 publications

Behavioral Testing of the Effects of Thermosensitive TRP Channel Agonists on Touch, Temperature, and Pain Sensations

Behavioral Testing of the Effects of Thermosensitive TRP Channel Agonists on Touch, Temperature, and Pain Sensations

Spinal 12-lipoxygenase-derived hepoxilin A₃contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors

Role of thermo TRPA1 and TRPV1 channels in heat, cold, and mechanical nociception of rats

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Behavioral evidence of thermal hyperalgesia and mechanical allodynia induced by intradermal cinnamaldehyde in rats

Cited by 43 publications

References 30 publications

Behavioral Testing of the Effects of Thermosensitive TRP Channel Agonists on Touch, Temperature, and Pain Sensations

Behavioral Testing of the Effects of Thermosensitive TRP Channel Agonists on Touch, Temperature, and Pain Sensations

Spinal 12-lipoxygenase-derived hepoxilin A3contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors

Role of thermo TRPA1 and TRPV1 channels in heat, cold, and mechanical nociception of rats

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Spinal 12-lipoxygenase-derived hepoxilin A₃contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors