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

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.

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

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.

Dopaminergic mechanisms in periaqueductal gray-mediated antinociception.

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.

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

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-HT1A or 3 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-HT1A or 3 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.

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

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.

Revealing a role of brainstem monoaminergic nuclei on the pronociceptive effect of sleep restriction.

Sleep disturbances and persistent pain conditions are public health challenges worldwide. Although it is well-known that sleep deficit increases pain sensitivity, the underlying mechanisms remain elusive. We have recently demonstrated the involvement of nucleus accumbens (NAc) and anterior cingulate cortex (ACC) in the pronociceptive effect of sleep restriction. In this study, we found that sleep restriction increases c-Fos expression in NAc and ACC, suggesting hyperactivation of these regions during prolonged wakefulness in male Wistar rats. Blocking adenosine A2A receptors in the NAc or GABAA receptors in the ventral tegmental area (VTA), dorsal raphe nucleus (DRN), or locus coeruleus (LC) effectively mitigated the pronociceptive effect of sleep restriction. In contrast, the blockade of GABAA receptors in each of these nuclei only transiently reduced carrageenan-induced hyperalgesia. Pharmacological activation of dopamine D2, serotonin 5-HT1A and noradrenaline alpha-2 receptors within the ACC also prevented the pronociceptive effect of sleep restriction. While pharmacological inhibition of these same monoaminergic receptors in the ACC restored the pronociceptive effect which had been prevented by the GABAergic disinhibition of the of the VTA, DRN or LC. Overall, these findings suggest that the pronociceptive effect of sleep restriction relies on increased adenosinergic activity on NAc, heightened GABAergic activity in VTA, DRN, and LC, and reduced inhibitory monoaminergic activity on ACC. These findings advance our understanding of the interplay between sleep and pain, shedding light on potential NAc-brainstem-ACC mechanisms that could mediate increased pain sensitivity under conditions of sleep impairment.

Impact of endogenous analgesia triggered by acupuncture, stress, or noxious stimulation on REM sleep-deprived rats.

Poor sleep increases pain, at least in part, by disrupting endogenous pain modulation. However, the efficacy of endogenous analgesia in sleep-deprived subjects has never been tested. To assess this issue, we chose three different ways of triggering endogenous analgesia: (1) acupuncture, (2) acute stress, and (3) noxious stimulation, and compared their ability to decrease the pronociceptive effect induced by REM-SD (Rapid Eye Movement Sleep Deprivation) with that to decrease inflammatory hyperalgesia in the classical carrageenan model. First, we tested the ability of REM-SD to worsen carrageenan-induced hyperalgesia: A low dose of carrageenan (30 µg) in sleep-deprived Wistar rats resulted in a potentiated hyperalgesic effect that was more intense and longer-lasting than that induced by a higher standard dose of carrageenan (100 µg) or by REM-SD alone. Then, we found that (1) acupuncture, performed at ST36, completely reversed the pronociceptive effect induced by REM-SD or by carrageenan; (2) immobilization stress completely reversed the pronociceptive effect of REM-SD, while transiently inhibited carrageenan-induced hyperalgesia; (3) noxious stimulation of the forepaw by capsaicin also reversed the pronociceptive effect of REM-SD and persistently increased the nociceptive threshold above the baseline in carrageenan-treated animals. Therefore, acupuncture, stress, or noxious stimulation reversed the pronociceptive effect of REM-SD, while each intervention affected carrageenan-induced hyperalgesia differently. This study has shown that while sleep loss may disrupt endogenous pain modulation mechanisms, it does not prevent the activation of these mechanisms to induce analgesia in sleep-deprived individuals.

Sleep and Pain: A Role for the Anterior Cingulate Cortex, Nucleus Accumbens, and Dopamine in the Increased Pain Sensitivity Following Sleep Restriction.

Persistent pain conditions and sleep disorders are public health problems worldwide. It is widely accepted that sleep disruption increases pain sensitivity; however, the underlying mechanisms are poorly understood. In this study, we used a protocol of 6 hours a day of total sleep deprivation for 3 days in rats to advance the understanding of these mechanisms. We focused on gender differences and the dopaminergic mesocorticolimbic system. The findings demonstrated that sleep restriction (SR) increased pain sensitivity in a similar way in males and females, without inducing a significant stress response. This pronociceptive effect depends on a nucleus accumbens (NAc) neuronal ensemble recruited during SR and on the integrity of the anterior cingulate cortex (ACC). Data on indirect dopaminergic parameters, dopamine transporter glycosylation, and dopamine and cyclic adenosine monophosphate (AMP)-regulated phosphoprotein-32 phosphorylation, as well as dopamine, serotonin, and norepinephrine levels, suggest that dopaminergic function decreases in the NAc and ACC after SR. Complementarily, pharmacological activation of dopamine D2, but not D1 receptors either in the ACC or in the NAc prevents SR from increasing pain sensitivity. The ACC and NAc are the main targets of dopaminergic mesocorticolimbic projections with a key role in pain modulation. This study showed their integrative role in the pronociceptive effect of SR, pointing to dopamine D2 receptors as a potential target for pain management in patients with sleep disorders. These findings narrow the focus of future studies on the mechanisms by which sleep impairment increases pain sensitivity. PERSPECTIVE: This study demonstrates that the pronociceptive effect of SR affects similarly males and females and depends on a NAc neuronal ensemble recruited during SR and on the integrity of the ACC. Findings on dopaminergic function support dopamine D2 receptors as targets for pain management in sleep disorders patients.

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

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 ß1 (atenolol, 6 µg/paw) or a ß2 (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.

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

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 E2 (PGE2) synthesis, but no previous study has investigated if it affects PGE2-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 PGE2 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 PGE2 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.

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

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.

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

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 (Cys2,Tyr3,Orn5,Pen7amide (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 GABAA 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.

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.

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).

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.