Publications by authors named "Luana Fischer"

27 Publications

  • Page 1 of 1

Short- and Long-Term Effects of Dietary Supplementation with Fish Oil on Inflammatory Pain in Rats.

J Am Coll Nutr 2021 Jun 22:1-9. Epub 2021 Jun 22.

Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil.

Introduction: Dietary supplementation with fish oil is promising as a complementary therapy for inflammatory pain. However, further studies are needed to support its therapeutic potential. For example, the antinociceptive effect of fish oil is widely suggested to be dependent on decreased prostaglandin E (PGE) synthesis, but no previous study has investigated if it affects PGE-induced nociceptive response. Similarly, beneficial long-term effects on inflammatory response are related to early exposure to fish oil, however, whether these effects include decreased inflammatory pain throughout life is not known.

Objective: The aim of this study was to investigate the short- and long-term effects of fish oil on inflammatory pain.

Methods: Dietary fish oil supplementation was performed through two protocols: in adult rats, during 20 days, or in dams, during pregnancy and lactation, with tests performed in adult offspring. The hyperalgesic response induced by carrageenan and its final mediators PGE and norepinephrine was used to model inflammatory pain.

Results: The findings demonstrated for the first time that dietary fish oil (1) decreases the hyperalgesia induced by carrageenan; (2) but not that induced by its final mediator PGE and norepinephrine; (3) increase omega-3 polyunsaturated fatty acids in peripheral neural tissue; and (4) attenuates inflammatory pain in individuals exposed to fish oil during pre-natal life and lactation.

Conclusion: Together, these findings support that fish oil decreases inflammatory pain either when consumed during adult life or during prenatal development. Future studies should confirm the therapeutic potential of fish oil in humans, which is essential for the development of public policies to encourage a fish oil richer diet.
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http://dx.doi.org/10.1080/07315724.2021.1911006DOI Listing
June 2021

Pain impairs consolidation, but not acquisition or retrieval of a declarative memory.

Behav Pharmacol 2020 12;31(8):707-715

Laboratory of Neurophysiology, Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana 81530-000, Brazil.

Among the physical conditions that impair memory performance, pain is one of the most prevalent. However, the mechanisms by which pain impairs memory are largely unknown. In this study, we asked whether pain affects memory acquisition, consolidation and retrieval as well as whether memory impairment depends on pain intensity. Wistar rats received a hind paw injection of formalin (1%) at different phases of object recognition test. The injection of formalin after training but not before training or testing impaired object recognition memory. We concluded that pain impairs the consolidation but not acquisition or retrieval of object recognition memory, which is a subtype of declarative memory. Morphine, at a dose that did not affect object recognition memory in control rats, drastically reduced formalin-induced nociceptive behavior without reversing memory impairment. A lower dose of formalin (0.25%) induced less nociceptive behavior, but similar memory impairment. There is no statistical correlation between the intensity of nociceptive response and the performance in object recognition test. However, when formalin-induced nociceptive response was blocked by a local anesthetic, memory impairment was prevented. These findings suggest that pain-induced impairment in the consolidation of object recognition memory does not directly depend on the intensity of nociceptive activity.
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http://dx.doi.org/10.1097/FBP.0000000000000576DOI Listing
December 2020

Contribution of mesolimbic dopamine and kappa opioid systems to the transition from acute to chronic pain.

Neuropharmacology 2020 11 6;178:108226. Epub 2020 Aug 6.

Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil. Electronic address:

Decreased dopaminergic activity and increased kappa opioid activity in the mesolimbic system underlie the negative emotional states related to chronic pain. However, it is not known whether these changes are just consequence of chronic pain or contribute to the sensorial changes associated with chronic pain. In this study, we asked whether the mesolimbic dopamine and kappa opioid systems contribute to the development and maintenance of chronic hyperalgesia, one of the most common sensorial changes related to chronic pain. The lesion of the dopaminergic cells of the ventral tegmental area prevented the transition from acute to chronic hyperalgesia when performed in pain-free rats, but did not affect the maintenance of chronic hyperalgesia, when performed in chronic pain in rats. As hyperalgesia becomes chronic, the dopamine levels in the nucleus accumbens decrease. The blockade of the kappa opioid receptors in the nucleus accumbens both prevented and reversed the development of chronic hyperalgesia, but did not affect its maintenance. Complementarily, the pharmacological activation of the kappa opioid receptors in the nucleus accumbens facilitated the transition from acute to chronic hyperalgesia. None of these interventions affected acute hyperalgesia. These findings suggest that the mesolimbic dopamine and kappa opioid systems specifically drive the pain chronification process, without affecting acute pain or the maintenance of chronic pain.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108226DOI Listing
November 2020

Pain and stress: functional evidence that supra-spinal mechanisms involved in pain-induced analgesia mediate stress-induced analgesia.

Behav Pharmacol 2020 04;31(2&3):159-167

Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba.

Analgesia induced by stressful and painful stimuli is an adaptive response during life-threatening situations. There is no evidence linking the mechanisms underlying them, while the former depends on the activation of stress-related brain pathways, the second depends on opioidergic mechanisms in the nucleus accumbens and on nicotinic cholinergic mechanisms in the rostral ventromedial medulla. In this study, we hypothesized that stress-induced analgesia is also dependent on opioidergic mechanisms in the nucleus accumbens and on nicotinic cholinergic mechanisms in the rostral ventromedial medulla. We used immobilization, a classical procedure to induce acute stress, and evaluated its ability to decrease the nociceptive responses induced either by carrageenan or by formalin in rats. Immobilization stress significantly decreased either carrageenan-induced hyperalgesia or formalin-induced tonic nociception in a time-dependent manner. This stress-induced analgesia is similar to pain-induced analgesia, as revealed by contrasting the antinociceptive effect induced by immobilization and by a forepaw injection of capsaicin. The administration of a µ-opioid receptor antagonist (CTOP, 0.5 µg) into the nucleus accumbens, as well as that of a nicotinic cholinergic receptor antagonist (mecamylamine, 0.6 µg) into the rostral ventromedial medulla, blocked immobilization stress-induced analgesia in both pain models. These results demonstrate that supraspinal mechanisms which are known to mediate pain-induced analgesia also mediate stress-induced analgesia. Therefore both forms of analgesia have overlapping mechanisms, probably recruited in response to the perception of danger.
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http://dx.doi.org/10.1097/FBP.0000000000000529DOI Listing
April 2020

Pain chronification and chronic pain impair a defensive behavior, but not the ability of acute pain to facilitate it, through the activation of an endogenous analgesia circuit.

Behav Neurosci 2018 Dec 4;132(6):614-623. Epub 2018 Oct 4.

Department of Physiology, Piracicaba Dental School, State University of Campinas.

The endogenous ability to decrease pain perception during life-threatening situations is crucial to the prevention of recuperative behaviors and to leave the subject free to engage in appropriated defensive responses. We have previously shown that acute pain activates the ascending nociceptive control-an endogenous analgesia circuit dependent on opioid mechanisms within nucleus accumbens-to facilitate the tonic immobility response, an innate defensive behavior. Now we asked whether chronic pain and pain chronification impairs either the tonic immobility response or the ability of acute pain to facilitate it by activating the ascending nociceptive control. We found a significant decrease in the duration of the tonic immobility response in rats during the induction and maintenance phases of the persistent mechanical hyperalgesia. This finding suggests that chronic pain and its development impair defensive responses. However, during the induction and maintenance phases of persistent hyperalgesia, the ascending nociceptive control activation, by a forepaw capsaicin injection, increased the tonic immobility response, an effect prevented by the blockade of μ-opioid receptors within nucleus accumbens. This finding suggests that pain chronification and chronic pain do not prevent the ability of acute pain to facilitate the defensive behavior of tonic immobility by activating the ascending nociceptive control. Therefore, although chronic pain states decrease the ability to engage in a defensive behavior, they may not prevent the expression of defensive behaviors during life-threatening situations accompanied by acute pain. The biological purpose of such a mechanism may be to increase the chances of survival of a wounded subject exposed to acute pain in a novel life-threatening situation. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
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http://dx.doi.org/10.1037/bne0000255DOI Listing
December 2018

Chronic sleep restriction increases pain sensitivity over time in a periaqueductal gray and nucleus accumbens dependent manner.

Neuropharmacology 2018 09 19;139:52-60. Epub 2018 Jun 19.

Neurophysiology Laboratory, Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil. Electronic address:

Painful conditions and sleep disturbances are major public health problems worldwide and one directly affects the other. Sleep loss increases pain prevalence and severity; while pain disturbs sleep. However, the underlying mechanisms are largely unknown. Here we asked whether chronic sleep restriction for 6 h daily progressively increases pain sensitivity and if this increase is reversed after two days of free sleep. Also, whether the pronociceptive effect of chronic sleep restriction depends on the periaqueductal grey and on the nucleus accumbens, two key regions involved in the modulation of pain and sleep-wake cycle. We showed that sleep restriction induces a pronociceptive effect characterized by a significant decrease in the mechanical paw withdrawal threshold in rats. Such effect increases progressively from day 3 to day 12 remaining stable thereafter until day 26. Two consecutive days of free sleep were not enough to reverse the effect, not even to attenuate it. This pronociceptive effect depends on the periaqueductal grey and on the nucleus accumbens, since it was prevented by their excitotoxic lesion. Complementarily, chronic sleep restriction significantly increased c-Fos protein expression within the periaqueductal grey and the nucleus accumbens and this correlates with the intensity of the pronociceptive effect, suggesting that the greater the neural activity in this regions, the greater the effect. These findings may contribute not only to understand why painful conditions are more prevalent and severe among people who sleep poorly, but also to develop therapeutic strategies to prevent this, increasing the effectiveness of pain management in this population.
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http://dx.doi.org/10.1016/j.neuropharm.2018.06.022DOI Listing
September 2018

Pain Inhibits Pain: an Ascending-Descending Pain Modulation Pathway Linking Mesolimbic and Classical Descending Mechanisms.

Mol Neurobiol 2019 Feb 1;56(2):1000-1013. Epub 2018 Jun 1.

Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil.

The ability to modulate pain perception is as critical to survival as pain itself. The most known pain modulation pathway is the PAG-RVM (periaqueductal gray-rostral ventromedial medulla) descending system. In this study, we hypothesized that it is functionally linked to the ascending nociceptive control, which is a form of pain-induced analgesia dependent on mesolimbic mechanisms. To test this hypothesis, we used a pharmacological approach, in which the antinociception induced by noxious stimulation (forepaw injection of capsaicin) was detected in a standard rat model of inflammatory pain (hindpaw injection of carrageenan). This antinociception was blocked by interventions known to block the ascending nociceptive control-mediated analgesia: the blockade of μ-opioid (Cys,Tyr,Orn,Penamide (CTOP) 0.5 μg) or of dopamine (SCH23390 1.8 μg and raclopride 5 μg) receptors within the NAc (nucleus accumbens) and that of cholinergic nicotinic receptors (mecamylamine 0.6 μg) within the RVM. The antinociception was also blocked by standard interventions known to block mechanisms of descending inhibition within either the PAG or the RVM: local acute neuronal blockade (lidocaine 2%), blockade of μ-opioid receptors (CTOP 0.5 μg), or activation of GABA receptors (muscimol 10 ng). Consistently, interventions that are known to block spinal mechanisms of descending inhibition also blocked antinociception: lesion of dorsolateral funiculus and the spinal blockade of serotonergic (WAY100135 46 μg or tropisetron 10 μg) or adrenergic (idazoxan, 50 μg) receptors. Neuronal activity indirectly estimated by c-Fos expression within the NAc, PAG, and RVM supports behavioral observations. Therefore, this study provides functional data indicating that noxious stimulation triggers an ascending-descending pain modulation pathway linking the mesolimbic system to the PAG-RVM descending system.
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http://dx.doi.org/10.1007/s12035-018-1116-7DOI Listing
February 2019

Reply.

Pain 2018 May;159(5):997-999

Division of Biological Sciences, Department of Physiology, Federal University of Parana, Curitiba, Parana, Brazil.

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http://dx.doi.org/10.1097/j.pain.0000000000001178DOI Listing
May 2018

Dopaminergic mechanisms in periaqueductal gray-mediated antinociception.

Behav Pharmacol 2018 04;29(2 and 3-Spec Issue):225-233

As important as perceiving pain is the ability to modulate this perception in some contextual salient situations. The periaqueductal gray (PAG) is perhaps the most important site of endogenous pain modulation; however, little is known about dopaminergic mechanisms underlying PAG-mediated antinociception. In this study, we used a pharmacological approach to evaluate this subject. We found that µ-opioid receptor-induced antinociception (DAMGO, 0.3 μg) from PAG was blocked by the coadministration of either D1-like or D2-like dopaminergic antagonists (SCH23390, 2, 4, and 6 μg or raclopride, 2 and 4 μg, respectively) both in the tail-flick and in the mechanical paw-withdrawal test. A selective D2-like receptor agonist (piribedil, 6 and 12 μg into the PAG) induced antinociception in the mechanical paw-withdrawal test, but not in the tail-flick test. This effect was blocked by the coadministration of its selective antagonist (raclopride 4 μg), as well as by either a GABAA agonist (muscimol, 0.1 μg) or an opioid receptor antagonist (naloxone, 0.5 μg). A selective D1-like receptor agonist (SKF38393, 1, 5, and 10 μg into the PAG) induced a poor and transient antinociceptive effect, but when combined with piribedil, a potentiated antinociceptive effect emerged. None of these treatments affected locomotion in the open-field test. These findings suggest that µ-opioid antinociception from the PAG depends on dopamine acting on both D1-like and D2-like receptors. Selective activation of PAG D2-like receptors induces antinociception mediated by supraspinal mechanisms dependent on inhibition of GABAA and activation of opioid neurotransmission.
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http://dx.doi.org/10.1097/FBP.0000000000000346DOI Listing
April 2018

Nucleus accumbens mediates the pronociceptive effect of sleep deprivation: the role of adenosine A2A and dopamine D2 receptors.

Pain 2018 01;159(1):75-84

Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil.

Sleep disorders increase pain sensitivity and the risk of developing painful conditions; however, the underlying mechanisms are poorly understood. It has been suggested that nucleus accumbens (NAc) influences sleep-wake cycle by means of a balance between adenosine activity at A2A receptors and dopamine activity at D2 receptors. Because the NAc also plays an important role in pain modulation, we hypothesized that the NAc and its A2A and D2 receptors mediate the pronociceptive effect of rapid eye movement (REM) sleep deprivation (SD). We found that 24 hours of REM-SD induced an intense pronociceptive effect in Wistar rats, which decreases progressively over a sleep rebound period. Although the level of fecal glucocorticoid metabolites increased with SD within group, it did not differ between sleep-deprived group and control group, indicating a stress response with similar magnitude between groups. The pronociceptive effect of REM-SD was prevented by excitotoxic lesion (N-Methyl-D-aspartate, 5.5 μg) of NAc and reverted by its acute blockade (Qx-314, 2%). The administration of an A2A receptor antagonist (SCH-58261, 7 ng) or a D2 receptor agonist (piribedil, 6 μg) into the NAc increased home cage activity and blocked the pronociceptive effect of REM-SD. Complementarily, an A2A receptor agonist (CGS-21680, 24 ng) impaired the reversal of the pronociceptive effect and decreased home cage activity, as it did a D2 receptor antagonist (raclopride, 5 μg). Rapid eye movement SD did not affect the expression of c-Fos protein in NAc. These data suggest that SD increases pain by increasing NAc adenosinergic A2A activity and by decreasing NAc dopaminergic D2 activity.
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http://dx.doi.org/10.1097/j.pain.0000000000001066DOI Listing
January 2018

Impact of excessive gingival display on oral health-related quality of life in a Southern Brazilian young population.

J Clin Periodontol 2017 Oct 25;44(10):996-1002. Epub 2017 Aug 25.

School of Dentistry, Franciscan University Center, Santa Maria, RS, Brazil.

Aim: To compare oral health-related quality of life (OHRQoL) between individuals with and without excessive gingival display (EGD).

Materials And Methods: A cross-sectional study was conducted in 53 individuals with EGD and 53 controls matched for sex and age. The outcome was OHRQoL, determined using the Oral Health Impact Profile (OHIP-14) and self-perceptions of satisfaction with smile aesthetics. A clinical examination was conducted to evaluate the smile line, colour of the teeth, tooth wear and malocclusion. Poisson regression was used to model the association between excessive gingival display and OHRQoL.

Results: Participants with EGD had higher total OHIP-14 score (4.81 ± 4.76) in comparison with the controls (1.85 ± 3.77; p < .001). The percentage of satisfied with smile individuals without and with EGD was 78.9% and 21.1%, respectively (p = .005). In the multivariate analysis, total OHIP-14 scores were 2.10-fold higher individuals with EGD, independently of the other variables analysed. Impacts were evident on the functional limitation, psychological discomfort, psychological disability and social handicap.

Conclusions: The occurrence of EGD exerted a negative impact on OHRQoL independently of confounding variables in this specific population. The present findings justify the planning of treatment for individuals with EGD that impacts quality of life.
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http://dx.doi.org/10.1111/jcpe.12753DOI Listing
October 2017

TRPA1, substance P, histamine and 5-hydroxytryptamine interact in an interdependent way to induce nociception.

Inflamm Res 2017 Apr 30;66(4):311-322. Epub 2016 Nov 30.

Department Functional and Structural Biology, Institute of Biology, State University of Campinas-UNICAMP, Campinas, São Paulo, Brazil.

Background: Although TRPA1, SP, histamine and 5-hydroxytryptamine (5-HT) have recognized contribution to nociceptive mechanisms, little is known about how they interact with each other to mediate inflammatory pain in vivo. In this study we evaluated whether TRPA1, SP, histamine and 5-HT interact, in an interdependent way, to induce nociception in vivo.

Methods And Results: The subcutaneous injection of the TRPA1 agonist allyl isothiocyanate (AITC) into the rat's hind paw induced a dose-dependent and short lasting behavioral nociceptive response that was blocked by the co-administration of the TRPA1 antagonist, HC030031, or by the pretreatment with antisense ODN against TRPA1. AITC-induced nociception was significantly decreased by the co-administration of selective antagonists for the NK1 receptor for substance P, the H1 receptor for histamine and the 5-HT receptors for 5-HT. Histamine- or 5-HT-induced nociception was decreased by the pretreatment with antisense ODN against TRPA1. These findings suggest that AITC-induced nociception depends on substance P, histamine and 5-HT, while histamine- or 5-HT-induced nociception depends on TRPA1. Most important, AITC interact in a synergistic way with histamine, 5-HT or substance P, since their combination at non-nociceptive doses induced a nociceptive response much higher than that expected by the sum of the effect of each one alone. This synergistic effect is dependent on the H1, 5-HT receptors.

Conclusion: Together, these findings suggest a self-sustainable cycle around TRPA1, no matter where the cycle is initiated each step is achieved and even subeffective activation of more than one step results in a synergistic activation of the overall cycle.
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http://dx.doi.org/10.1007/s00011-016-1015-1DOI Listing
April 2017

Coactivation of μ- and κ-Opioid Receptors May Mediate the Protective Effect of Testosterone on the Development of Temporomandibular Joint Nociception in Male Rats.

J Oral Facial Pain Headache 2016 ;30(1):61-7

Aims: To investigate whether the protective effect of testosterone on the development of temporomandibular joint (TMJ) nociception in male rats is mediated by the activation of central opioid mechanisms.

Methods: Experiments were performed on 156 male Wistar rats. A pharmacologic approach was used to assess the ability of opioid receptor antagonists infused into the dorsal portion of the brainstem and adjacent to the caudal component (subnucleus caudalis) of the spinal trigeminal nucleus to block the protective effect of testosterone in male rats. The TMJ injection of 0.5% formalin was used as a nociceptive stimulus. One-way or two-way ANOVA was used for data analyses.

Results: The injection of 0.5% formalin into the TMJ induced a significant nociceptive behavior in gonadectomized male rats (P < .05), but not in naïve, sham, and testosterone-replaced gonadectomized rats, confirming that testosterone prevents the development of TMJ nociception. The injection of either the nonselective opioid receptor antagonist naloxone (15 μg) or the simultaneous injection of the μ-opioid receptor antagonist Cys2, Tyr3, Orn5, Pen7amide (CTOP, 30 μg) and the κ-opioid receptor antagonist Nor-Binaltorphimine (Nor-BNI, 90 μg) significantly increased the 0.5% formalin-induced behavioral response in sham and testosterone-replaced gonadectomized rats (P < .05) but had no effect in gonadectomized rats. However, the injection of each selective opioid receptor antagonist alone or the simultaneous injection of μ- or κ- and δ-opioid receptor antagonists had no effect.

Conclusion: These findings indicate that the protective effect of endogenous testosterone on the development of TMJ nociception in male rats is mediated by the activation of central opioid mechanisms. Furthermore, the coactivation of central μ- and κ-opioid receptors is necessary for testosterone to protect male rats from developing TMJ nociception.
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http://dx.doi.org/10.11607/ofph.1298DOI Listing
March 2016

The Pronociceptive Effect of Paradoxical Sleep Deprivation in Rats: Evidence for a Role of Descending Pain Modulation Mechanisms.

Mol Neurobiol 2016 Apr 24;53(3):1706-1717. Epub 2015 Feb 24.

Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil.

The mechanisms underlying the pronociceptive effect of paradoxical sleep deprivation (PSD) are not known. In this study, we asked whether PSD increases tonic nociception in the formalin test, decreases the antinociceptive effect of morphine administered into the periaqueductal gray matter (PAG), and disrupts endogenous descending pain modulation. PSD for either 24 or 48 h significantly increased formalin-induced nociception and decreased mechanical nociceptive paw withdrawal threshold. The maximal antinociceptive effect induced by morphine (0.9-9 nmol, intra-PAG) was significantly decreased by PSD. The administration of a low dose of the GABAA receptor antagonist, bicuculline (30-300 pmol, intra-PAG), decreased nociception in control rats, but not in paradoxical-sleep-deprived ones. Furthermore, the administration of the cholecystokinin (CCK) 2 receptor antagonist, YM022 (0.5-2 pmol) in the rostral ventral medulla (RVM), decreased nociception in paradoxical-sleep-deprived rats but not in control ones. While a dose of the CCK 2 receptor agonist, CCK-8 (8-24 pmol intra-RVM), increased nociception in control rats, but not in paradoxical-sleep-deprived ones. In addition, the injection of lidocaine (QX-314, 2%, intra-RVM) decreased nociception in sleep-deprived rats, but not in control rats, while the lesion of the dorsolateral funiculus prevented the pronociceptive effect of PSD. Finally, PSD significantly increased c-Fos expression in the RVM. Therefore, PSD increases pain independently of its duration or of the characteristic of the nociceptive stimulus and decreases morphine analgesia at the PAG. PSD appears to increase pain by decreasing descending pain inhibitory activity and by increasing descending pain facilitatory activity.
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http://dx.doi.org/10.1007/s12035-014-9059-0DOI Listing
April 2016

The contribution of transient receptor potential ankyrin 1 (TRPA1) to the in vivo nociceptive effects of prostaglandin E₂.

Life Sci 2014 Jun 6;105(1-2):7-13. Epub 2014 Mar 6.

Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil. Electronic address:

Aims: Although evidence suggest that TRPA1 mediates some effects of prostaglandins, it is not known whether TRPA1 contributes to the in vivo nociceptive effects of prostaglandin E2 (PGE2), a key mediator of inflammatory pain.

Main Methods: To address this issue, the effect of the pharmacological blockade of TRPA1 or of its gene silencing on the hyperalgesia induced in the rat paw by PGE2 or its downstream signaling molecules, protein kinase A (PKA) or protein kinase C-epsilon (PKCε), was evaluated. TRPA1 expression on dorsal root ganglia cells was assessed by western blot.

Key Findings: The pharmacological blockade of local TRPA1 by its selective antagonist, HC 030031 decreased and reversed PGE2-induced hyperalgesia. The TRPA1 gene silencing induced by intrathecal pre-treatment with antisense oligodeoxynucleotide blocked PGE2-induced hyperalgesia and strongly reduced TRPA1 expression in dorsal root ganglia cells (L5 and L6). PGE2 injection into the hind paw did not significantly increase TRPA1 expression in dorsal root ganglia cells. Treatment with either HC 030031 or antisense oligodeoxynucleotide significantly decreased the hyperalgesia induced by PKA or PKCε. Since both kinases are the major components of PGE2-induced intracellular signal transduction, the modulation of TRPA1 function by PGE2 may be downstream PKA and PKC-epsilon.

Significance: These findings show that TRPA1 is essential to the in vivo nociceptive effects induced by one of the most important mediators of inflammatory pain, PGE2. This is one of the crucial findings necessary to support TRPA1 as a promising target for the development of future drugs to pain treatment and control.
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http://dx.doi.org/10.1016/j.lfs.2014.02.031DOI Listing
June 2014

Ascending nociceptive control contributes to the antinociceptive effect of acupuncture in a rat model of acute pain.

J Pain 2014 Apr 9;15(4):422-34. Epub 2014 Jan 9.

Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil. Electronic address:

Unlabelled: Acupuncture-induced analgesia depends on the activation of endogenous pain modulation pathways. In this study, we asked whether ascending nociceptive control (ANC), a form of pain-induced analgesia, contributes to the antinociceptive effect of acupuncture. To answer this question, we tested the ability of procedures that block ANC-induced analgesia, at peripheral, spinal, nucleus accumbens and rostral ventral medulla levels, to block acupuncture-induced analgesia. Acupuncture at ST36 (Zusanli), a widely used acupoint located in the hind limb, induced potent heterosegmental antinociception in the orofacial formalin test. The magnitude of this antinociceptive effect was similar to that induced by an intraplantar injection of capsaicin, a procedure classically used to activate ANC. The antinociceptive effect of acupuncture was blocked by sciatic C-fibers depletion (1% perineural capsaicin), spinal administration of a μ-opioid (Cys2,Tyr3,Orn5,Pen7amide, .2 μg) or of a GABAA (bicuculline, .3 μg) receptor antagonist, intra-nucleus accumbens administration of a μ-opioid receptor antagonist (Cys2,Tyr3,Orn5,Pen7amide, 1 μg), or intrarostral ventral medulla administration of a nicotinic acetylcholine receptor antagonist (mecamylamine, .6 μg). In addition, acupuncture at ST36 and/or upper lip formalin induced c-Fos expression in the nucleus accumbens and in rostral ventral medulla. On the basis of these results, we propose that ANC contributes to the antinociceptive effect of acupuncture.

Perspective: This article presents a novel mechanism of acupuncture analgesia, contributing to the understanding of its scientific basis. Because ANC is a pain modulation pathway activated by peripheral noxious stimulation that ascends to supraspinal regions, it could be the link between acupoint stimulation and the central mechanisms underlying acupuncture analgesia.
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http://dx.doi.org/10.1016/j.jpain.2013.12.008DOI Listing
April 2014

Dopaminergic D2 receptor is a key player in the substantia nigra pars compacta neuronal activation mediated by REM sleep deprivation.

Neuropharmacology 2014 Jan 4;76 Pt A:118-26. Epub 2013 Sep 4.

Laboratório de Neurofisiologia, Departamento de Fisiologia, Universidade Federal do Paraná, Setor de Ciências Biológicas, Av. Francisco H. dos Santos s/n, 81.531-990, Caixa Postal 19031, Curitiba, PR, Brazil.

Currently, several studies addresses the novel link between sleep and dopaminergic neurotransmission, focusing most closely on the mechanisms by which Parkinson's disease (PD) and sleep may be intertwined. Therefore, variations in the activity of afferents during the sleep cycles, either at the level of DA cell bodies in the ventral tegmental area (VTA) and/or substantia nigra pars compacta (SNpc) or at the level of dopamine (DA) terminals in limbic areas may impact functions such as memory. Accordingly, we performed striatal and hippocampal neurochemical quantifications of DA, serotonin (5-HT) and metabolites of rats intraperitoneally treated with haloperidol (1.5 mg/kg) or piribedil (8 mg/kg) and submitted to REM sleep deprivation (REMSD) and sleep rebound (REB). Also, we evaluated the effects of REMSD on motor and cognitive parameters and SNpc c-Fos neuronal immunoreactivity. The results indicated that DA release was strongly enhanced by piribedil in the REMSD group. In opposite, haloperidol prevented that alteration. A c-Fos activation characteristic of REMSD was affected in a synergic manner by piribedil, indicating a strong positive correlation between striatal DA levels and nigral c-Fos activation. Hence, we suggest that memory process is severely impacted by both D2 blockade and REMSD and was even more by its combination. Conversely, the activation of D2 receptor counteracted such memory impairment. Therefore, the present evidence reinforce that the D2 receptor is a key player in the SNpc neuronal activation mediated by REMSD, as a consequence these changes may have direct impact for cognitive and sleep abnormalities found in patients with PD. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.
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http://dx.doi.org/10.1016/j.neuropharm.2013.08.024DOI Listing
January 2014

Mechanisms underlying transient receptor potential ankyrin 1 (TRPA1)-mediated hyperalgesia and edema.

J Peripher Nerv Syst 2013 Mar;18(1):62-74

Department of Physiology, Laboratory of Pain Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil.

The aim of this study was to investigate the mechanisms that contribute to hyperalgesia and edema induced by TRPA1 activation. The injection of allyl isothiocyanate (AITC, 50, 100, or 300 µg/paw) into the rat's hind paw induced dose and time-dependent hyperalgesia and edema, which were blocked by the selective TRPA1 antagonist, HC 030031 (1,200 µg/paw), or by treatment with antisense oligodeoxynucleotide (four daily intrathecal injections of 5 nmol). These results demonstrate that the hyperalgesia and edema induced by AITC depend on TRPA1 activation. AITC-induced hyperalgesia and edema were significantly reduced by treatment with neurokinin 1 (L-703,606, 38 µg/paw) or calcitonin gene-related peptide (CGRP8-37 , 5 µg/paw) receptor antagonists, with a mast cell degranulator (compound 48/80, four daily injections of 1, 3, 10, and 10 µg/paw) or with H1 (pyrilamine, 400 µg/paw), 5-HT1A (wAy-100,135, 450 µg/paw) or 5-HT3 (tropisetron, 450 µg/paw) receptor antagonists. Pre-treatment with a selectin inhibitor (fucoidan, 20 mg/kg) significantly reduced AITC-induced hyperalgesia, edema, and neutrophil migration. Finally, a cyclooxygenase inhibitor (indomethacin, 100 µg/paw), a β1 (atenolol, 6 µg/paw) or a β2 (ICI 118, 551, 1.5 µg/paw) adrenoceptor antagonist also significantly reduced AITC-induced hyperalgesia and edema. Together, these results demonstrate that TRPA1 mediates some of the key inflammatory mechanisms, suggesting a key role of this receptor in pain and inflammation.
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http://dx.doi.org/10.1111/jns5.12010DOI Listing
March 2013

The role of transient receptor potential A 1 (TRPA1) in the development and maintenance of carrageenan-induced hyperalgesia.

Neuropharmacology 2013 Feb 23;65:206-12. Epub 2012 Oct 23.

Department of Functional and Structural Biology, Institute of Biology, State University of Campinas - UNICAMP, Campinas, São Paulo, Brazil.

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective cation channel important in setting nociceptive threshold. It is expressed in nociceptive C-fibers and in non-neuronal cells involved in pro-inflammatory mediators' release. We asked whether TRPA1 contributes to carrageenan-induced hyperalgesia in rats, and if so, whether this contribution is mediated by mechanisms involved in inflammation such as cytokine release and neutrophil migration and/or by a direct sensitization of the primary afferent nociceptors. Pharmacological blockade of local TRPA1 by its selective antagonist HC 030031 prevented and reversed carrageenan-induced hyperalgesia, which was detected either by a mechanical or chemical (low dose of capsaicin) stimulus. However, it did not affect either carrageenan-induced cytokines expression or neutrophil migration. The neuronal TRPA1 gene silencing induced by intrathecal pre-treatment with antisense oligodoexynucleotide completely prevented carrageenan-induced hyperalgesia over 24 h and significantly reduced TRPA1 expression in the dorsal root ganglia cells (L5-6), which was not affected by carrageenan treatment. We conclude that TRPA1 plays an important role in the development and maintenance of carrageenan-induced inflammatory hyperalgesia by directly contributing to nociceptor excitability.
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http://dx.doi.org/10.1016/j.neuropharm.2012.09.020DOI Listing
February 2013

The functional role of ascending nociceptive control in defensive behavior.

Brain Res 2012 Jun 14;1464:24-9. Epub 2012 May 14.

Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas, SP, Brazil.

Ascending nociceptive control is a novel spino-striato-rostral ventral medulla pain modulation pathway that mediates heterosegmental pain-induced analgesia, i.e., noxious stimulus-induced antinociception. In this study, we used the dorsal immobility response in rats as a model of the defensive responses. We demonstrated that the activation of ascending nociceptive control by peripheral noxious stimulation and spinal AMPA and mGluR1 receptor blockade significantly potentiated the duration of the dorsal immobility response in rats via an opioid-dependent mechanism in the nucleus accumbens. These results demonstrated the functional role of ascending nociceptive control in the modulation of defensive responses and spinal glutamatergic receptors in the dorsal immobility response. The immobility response is an antipredator behavior that reflects the underlying state of fear, and ascending nociceptive control may modulate fear.
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http://dx.doi.org/10.1016/j.brainres.2012.05.010DOI Listing
June 2012

Local kappa opioid receptor activation decreases temporomandibular joint inflammation.

Inflammation 2012 Feb;35(1):371-6

Department of Physiology, Piracicaba Dental School, State University of Campinas-UNICAMP, Piracicaba, São Paulo, Brazil.

In an attempt to decrease central side effects associated with the use of opioids, some strategies have been developed by targeting peripheral opioid receptors. In this context, kappa receptors are of major interest, since, in contrast to other opioid receptors, their activation is not associated with potent peripheral side effects. We have recently demonstrated that local activation of kappa opioid receptors significantly decreases formalin-induced temporomandibular joint nociception; however, whether it also decreases temporomandibular joint inflammation is not known. To address this issue, we evaluated if a specific kappa opioid receptor agonist, U50,488 (trans-(1S,2S)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide hydrochloride hydrate), administered into the temporomandibular joint decreases formalin-induced plasma extravasation and neutrophil migration. Ipsilateral, but not contralateral, administration of U50,488 into the temporomandibular joint blocked formalin-induced plasma extravasation and neutrophil migration in a dose-dependent manner. This anti-inflammatory effect was reversed by the ipsilateral, but not contralateral, administration of the kappa opioid receptor antagonist nor-BNI (nor-binaltorphimine dihydrochloride). This study demonstrates that local activation of kappa opioid receptors decreases two important parameters of temporomandibular joint inflammation, that is, plasma extravasation and neutrophil migration, in a dose-dependent and antagonist-reversible manner. This anti-inflammatory effect taken together with the potent antinociceptive effect, suggests that drugs targeting peripheral kappa opioid receptors are promising for the treatment of inflammatory temporomandibular joint pain and probably, other articular pain conditions with an inflammatory basis.
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http://dx.doi.org/10.1007/s10753-011-9329-1DOI Listing
February 2012

Sexual dimorphism on cytokines expression in the temporomandibular joint: the role of gonadal steroid hormones.

Inflammation 2011 Oct;34(5):487-98

Laboratory of Orofacial Pain, Department of Physiology, Faculty of Dentistry of Piracicaba, State University of Campinas-UNICAMP, Av. Limeira 901, CEP 13414-900, Piracicaba, São Paulo, Brazil.

Temporomandibular joint pain-related conditions are generally characterized by local inflammation; however, little studies have focused on the role of gonadal hormones in the expression of inflammatory mediators, such as cytokines. Therefore, we asked whether gonadal steroid hormones affect formalin-induced cytokines expression in the rat temporomcandibular joint. The expression of tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and cytokine-induced neutrophil chemoattractant (CINC)-1 was significantly higher in males than in diestrus and proestrus females and was decreased by orchiectomy and restored by testosterone replacement. The expression of IL-6 was significantly higher in diestrus and proestrus females than in males, and was decreased by ovariectomy and restored by estradiol or progesterone administration. We conclude that testosterone increases the expression of TNF-α, IL-1β and CINC-1, and estradiol and progesterone increase the expression of IL-6. New clinical approaches based on inhibition of pro-inflammatory mediators are starting to supplant traditional immunosuppressive therapies and gonadal hormones may influence their effectiveness or clinical dosage.
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http://dx.doi.org/10.1007/s10753-010-9256-6DOI Listing
October 2011

Contribution of endogenous opioids to gonadal hormones-induced temporomandibular joint antinociception.

Behav Neurosci 2009 Oct;123(5):1129-40

Laboratory of Pain Physiology, Division of Biological Sciences, Department of Physiology, Federal University of Parana, Curitiba, Parana, Brazil.

The authors have recently demonstrated that the high serum estradiol level during the proestrus phase of the estrous cycle and that the administration of estradiol or progesterone in ovariectomized female and of testosterone in orchiectomized male rats significantly decrease formalin-induced temporomandibular joint (TMJ) nociception. In this study, the authors investigate the contribution of endogenous opioids to this antinociceptive effect of gonadal hormones in the TMJ formalin test. The opioid receptor antagonist naloxone was administrated either in the surrounding of the trigeminal sensory complex or in the TMJ region. The antinociceptive effect induced by endogenous estradiol in proestrus females and by exogenous estradiol in ovariectomized females was blocked by the administration of naloxone in the surrounding of the trigeminal sensory complex, but not in the TMJ region. The antinociceptive effect induced by the administration of progesterone in ovariectomized females and of testosterone in orchiectomized males was blocked by the administration of naloxone either in the surrounding of the trigeminal sensory complex or in the TMJ region. The authors conclude that central and peripheral opioid mechanisms mediate the antinociceptive effect of progesterone and testosterone, and central opioid mechanisms mediate the antinociceptive effect of estradiol. These findings suggest that the enhanced pain perception during low gonadal hormone periods in women and animals may be mediated by a decrease in endogenous opioid activity. This suggestion helps explain the higher severity of some pain conditions, such as temporomandibular dysfunctions in women than in men, that have no hormonal fluctuations.
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http://dx.doi.org/10.1037/a0017063DOI Listing
October 2009

The influence of sex and ovarian hormones on temporomandibular joint nociception in rats.

J Pain 2008 Jul;9(7):630-8

Laboratory of Orofacial Pain, Department of Physiology, Faculty of Dentistry of Piracicaba, State University of Campinas-UNICAMP, São Paulo, Brazil.

Unlabelled: The aim of this study was to investigate the influence of sex and ovarian hormones on formalin- and glutamate-induced temporomandibular joint (TMJ) nociception in rats. The influence of sex and ovarian hormones on the nociceptive behavior induced by formalin or glutamate was virtually the same. The nociceptive behavior of males was similar to that of females in the proestrus phase of the estrous cycle but was significantly lower than that in the diestrus phase. Since the serum level of estradiol but not of progesterone was significantly higher in the proestrus than in the diestrus phase, these data suggest that females with lower endogenous serum level of estradiol have an exacerbation of TMJ nociception. The nociceptive behavior of ovariectomized rats was similar to that of diestrus females and significantly greater than that of proestrus females. Although the administration of estradiol or progesterone in ovariectomized females significantly reduced TMJ nociception, the combination of both hormones did not increase the antinociceptive effect induced by each of them. These findings suggest that estradiol and progesterone decrease TMJ nociception in an independent way.

Perspective: We report that ovarian hormones have an antinociceptive effect on the TMJ formalin and glutamate nociceptive behavior models. Therefore, the greater prevalence and severity of TMJ pain in women of reproductive age may be a consequence of hormonal fluctuation during the reproductive cycle, in that during low endogenous estradiol serum level TMJ pain sensitivity is increased, enhancing the risk of females experiencing TMJ pain.
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http://dx.doi.org/10.1016/j.jpain.2008.02.006DOI Listing
July 2008

Involvement of peripheral TRPV1 in TMJ hyperalgesia induced by ethanol withdrawal.

Life Sci 2007 Nov 10;81(23-24):1622-6. Epub 2007 Oct 10.

Laboratory of Orofacial Pain, Division of Oral Physiology, Piracicaba Dental School, University of Campinas-Unicamp, Av. Limeira 901 C.P. 52, CEP 13414-900, Piracicaba, São Paulo, Brazil.

Ethanol withdrawal increases nociception after the injection of formalin into the rat's temporomandibular joint (TMJ). Little is known about the neurological basis for hyperalgesia induced by ethanol withdrawal, but it has been reported that ethanol can potentiate the response of transient receptor potential vanilloid receptor-1 (TRPV1) in superficial tissues. The present study was designed to test the hypothesis that peripheral TRPV1 could be involved on nociceptive behavioral responses induced by the injection of formalin into the TMJ region of rats exposed to chronic ethanol administration and ethanol withdrawal. Behavioral hyperalgesia was verified 12 h after ethanol withdrawal in rats that drank an ethanol solution (6.5%) for 10 days. In another group submitted to the same ethanol regimen, the selective vanilloid receptor antagonist capsazepine (300, 600 or 1200 microg/25 microl) or an equal volume of vehicle were injected into the TMJ regions 30 min before the TMJ formalin test. The local injections of capsazepine reduced the increased nociceptive responses induced by ethanol withdrawal. The effect of capsazepine on rats that did not drink ethanol was not significant. These results indicate that the peripheral TRPV1 can contribute to the hyperalgesia induced by ethanol withdrawal on deep pain conditions.
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http://dx.doi.org/10.1016/j.lfs.2007.10.002DOI Listing
November 2007

The protective role of testosterone in the development of temporomandibular joint pain.

J Pain 2007 May 13;8(5):437-42. Epub 2007 Mar 13.

Laboratory of Orofacial Pain, Department of Physiology, Faculty of Dentistry of Piracicaba, University of Campinas-Unicamp, São Paulo, Brazil.

Unlabelled: The lower prevalence of many pain conditions, including temporomandibular dysfunctions, in men than in women has not as yet been clarified. The aim of this study was to investigate the effect of testosterone on the risk of development of temporomandibular joint (TMJ) pain and on acute persistent TMJ pain. The TMJ formalin test was used as an experimental assay in the rat. Intra-TMJ 0.5% formalin induced a significant nociceptive behavior in naive female rats and gonadectomized male rats but not in naive male rats, suggesting that naive male rats have a lower risk for development of TMJ pain. The finding that the serum level of testosterone but not of estrogen and progesterone significantly decreased in gonadectomized male rats suggests that testosterone is the hormone underlying the decreased naive male rat's risk for development of TMJ pain. The magnitude of the nociceptive behaviors induced by intra-TMJ 1.5% formalin was similar in gonadectomized and naive male rats. Therefore, in contrast to the protective role of testosterone in TMJ pain development, testosterone, at physiological serum levels, does not appear to modulate acute persistent TMJ pain induced by the TMJ injection of 1.5% formalin. At a supraphysiological serum level, however, testosterone significantly attenuated 1.5% formalin-induced nociception in male rats but not in female rats. This antinociceptive effect was not mediated by estrogen derived from testosterone aromatization, because estrogen administration did not affect 1.5% formalin-induced TMJ nociception in gonadectomized male rats.

Perspective: The present findings not only help to explain the lower prevalence of TMJ pain in males versus females but also show that testosterone reduces TMJ pain at supraphysiological serum levels.
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http://dx.doi.org/10.1016/j.jpain.2006.12.007DOI Listing
May 2007

A novel method for subarachnoid drug delivery in the medullary region of rats.

J Neurosci Methods 2005 Oct 15;148(2):108-12. Epub 2005 Jul 15.

Laboratory of Orofacial Pain, Department of Physiology, Faculty of Dentistry of Piracicaba, University of Campinas-Unicamp, Av. Limeira 901, CEP 13414-900, Piracicaba, São Paulo, Brazil.

This study describes a novel method for direct subarachnoid drug delivery to the medullary dorsal horn region of rats, without introducing a catheter. The reliability of the method was demonstrated by a pharmacological validation; that is, morphine administration to the medullary region blocked the nociceptive response to formalin injected in the temporomandibular joint (TMJ) region, an effect that was prevented by co-administration of naloxone. The method proposed offers many advantages over the existing methods for medullary drug delivery with catheter implantation. It is easy to be employed, it does not induce any sign of motor impairment, and it does not require the neck surgery performed to implant a catheter in the medullary dorsal horn region. Therefore, it is a useful method for subarachnoid drug delivery in behavioral trigeminal pain studies, particularly when nociceptive behavioral measures that require normal neck muscle activity to occur, such as head withdraw or head flinch, are evaluated.
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http://dx.doi.org/10.1016/j.jneumeth.2005.04.021DOI Listing
October 2005
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