Maria Cecília Ferraz de Arruda Veiga

How may stressful experiences contribute to the development of temporomandibular disorders

Temporomandibular disorders (TMD) comprise the most common cause of chronic facial pain conditions, and they are often associated with somatic and psychological complaints including fatigue, sleep disturbances, anxiety, and depression. For many health professionals, the subjectivity of pain experience is frequently neglected even when the clinic does not find any plausible biologic explanation for the pain. This strictly biomedical vision of pain cannot be justified scientifically. The purpose of this study is to demonstrate, by original articles from the literature and recent studies conducted in our own laboratory, the biological processes by which psychological stress can be translated into the sensation of pain and contribute to the development of TMD. The role of the hypothalamic–pituitary–adrenal axis, the serotoninergic and opioid systems in the pathogenesis of facial pain is exposed, including possible future therapeutic approaches. It is hoped that knowledge from apparently disparate fields of dentistry, integrated into a multidisciplinary clinical approach to TMD, will improve diagnosis and treatment for this condition through a clinical practice supported by scientific knowledge.

Sexual dimorphism in the antinociception mediated by kappa opioid receptors in the rat temporomandibular joint

This study assessed the effect of the kappa opioid receptor agonist U50,488 administered into the rat temporomandibular joint (TMJ) on nociceptive behavioral responses evoked by formalin injected into the same site. Groups consisted of females, stratified into proestrus and diestrus phases of the estrous cycle, and males. Intra-TMJ formalin induced significantly different dose-dependent responses among the three groups, with diestrus females showing greater responses than males or proestrus females; therefore, equi-nociceptive formalin doses were chosen to test the effects of U50,488. U50,488 significantly reduced formalin-induced nociceptive behavior in all groups, but the reduction was significantly greater in females, especially those in diestrus. Pre-injection of the selective kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI) into the same site significantly attenuated the effect of U50488; U50,488 injection into the contralateral TMJ failed to reduce nociceptive behavior. These findings support a role for kappa opioid receptors local to the site of inflammation to modulate inflammatory pain. Furthermore, since plasma levels of ovarian hormones are low during diestrus, these findings are consistent with the suggestion that sex hormones may play an antagonistic role in these peripheral kappa-mediated effects.

Evidence for the involvement of endogenous ATP and P2X receptors in TMJ pain

Evidence is accumulating which supports a role for ATP in the initiation of pain by acting on P2X receptors expressed on nociceptive afferent nerve terminals. To investigate whether these receptors play a role in temporomandibular (TMJ) pain, we studied the presence of functional P2X receptors in rat TMJ by examining the nociceptive behavioral response to the application of the selective P2X receptor agonist α,β‐methylene ATP (α,β‐meATP) into the TMJ region of rat. The involvement of endogenous ATP in the development of TMJ inflammatory hyperalgesia was also determined by evaluating the effect of the general P2 receptor antagonist pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS) on carrageenan‐induced TMJ inflammatory hyperalgesia. Application of α,β‐meATP into the TMJ region of rats produced significant nociceptive responses that were significantly reduced by the co‐application of lidocaine N‐ethyl bromide quaternary salt, QX‐314, (2%) or of the P2 receptor antagonist PPADS. Co‐application of PPADS with carrageenan into the TMJ significantly reduced inflammatory hyperalgesia. The results indicate that functional P2X receptors are present in the TMJ and suggest that endogenous ATP may play a role in TMJ inflammatory pain mechanisms possibly by acting primarily in these receptors.

The Influence of Sex and Ovarian Hormones on Temporomandibular Joint Nociception in Rats

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.

The effects of restraint stress on nociceptive responses induced by formalin injected in rat's TMJ

It has been reported that stress can alter nociception from superficial tissues, such as skin and subcutaneous region. However, the influence of stress on an experimental deep nociception model is not understood. In this study, the temporomandibular joint (TMJ) formalin test was used to evaluate the effects of acute and chronic restraint stress on nociceptive responses in rats. Animals were initially submitted to one session of acute restraint stress (1 h) or exposed to chronic stress (40 days-1 h/day). Then, animals were killed immediately to collect blood for hormonal determinations by radioimmunoassay, or submitted to the TMJ formalin test to evaluate nociception. Rats submitted to acute restraint presented a performance similar to unstressed controls in the TMJ formalin test, whereas chronically stressed rats showed an increase in nociceptive responses. After 40 days of restraint, morphine was injected i.p. (1, 5 mg/kg or saline). The stressed rats displayed decreased morphine effects on nociception compared to unstressed controls. These findings suggest that repeated stress can produce hyperalgesia, which is, at least in part, due to alterations in the activity of opioid systems. This model may help elucidate the underlying neural mechanisms that mediate the effects of repeated stress on orofacial pain.

The effects of acute restraint stress on nociceptive responses evoked by the injection of formalin into the temporomandibular joint of female rats

The temporomandibular joint (TMJ) formalin test was used to evaluate the effects of acute restraint stress on the nociceptive behavioral responses of female rats during proestrus and estrus phases of the estrous cycle. Rats were subjected to one session of restraint stress (15, 30 min or 1 h). They were then either immediately killed to allow the collection of blood for hormonal radioimmunoassay determinations or subjected to TMJ formalin test to evaluate nociception. All stress protocols significantly raised the plasma concentrations of corticosterone. The performance of rats subjected to 15 and 30 min of restraint stress was similar to that of control rats, whereas rats that were stressed for 1 h showed a decrease in nociceptive responses, during both proestrus and estrus phases. The stress-induced analgesia (SIA) was greater in the proestrus phase. To evaluate the role of κ-opioid receptors, the selective receptor κ-opioid antagonist nor-binaltorphimine (nor-BNI; 200 μg or saline) was injected into the TMJ 24 h prior to the 1 h stress period and the TMJ formalin test. The local administration of nor-BNI partially reversed the SIA during the proestrus phase. These findings suggest that (1) acute stress for 1 h can produce analgesia both during proestrus and estrus phases; this effect is greater during the proestrus phase and (2) κ-opioid receptor activation is involved in the SIA observed in the proestrus phase.

Nociceptive behavior induced by mustard oil injection into the temporomandibular joint is blocked by a peripheral non-opioid analgesic and a central opioid analgesic

The aim of this study was to improve the mustard oil (MO) induced temporomandibular joint (TMJ) nociception model and to investigate the potential analgesic activity of systemic dipyrone and tramadol on the nociceptive behavioral responses induced by injection of low concentrations of the MO into the rat TMJ region. TMJ injection of 2.5% MO produced a significant nociceptive behavior expressed by head flinching and orofacial rubbing. This activity was related to the MO injection since mineral oil (vehicle) did not elicit response. Local application of the lidocaine N-ethyl bromide quaternary salt, QX-314 (2%) and systemic administration of morphine (4 mg/kg) significantly reduced the MO-induced nociceptive responses, validating the nociceptive character of the behaviors. The pretreatment with systemic dipyrone (19, 57 or 95 mg/kg) as well as tramadol (5, 7.5 or 10 mg/kg) was effective in decreasing the nociceptive behavioral responses induced by the injection of MO into the rat TMJ. In conclusion, TMJ injection of low concentrations of MO in rats produces well defined and quantifiable nociceptive behaviors constituting a reliable behavioral model for studying TMJ pain mechanisms and testing analgesic drugs. The results also suggest that dipyrone and tramadol could be effective analgesic options in the management of TMJ pain.

Influence of orofacial pain, in superficial and deep tissue, on the anxiety levels in rats

Purpose: The present study aimed to determine the influence of orofacial pain in superficial and deep tissue on anxiety levels in male Wistar rats. Methods: Orofacial pain was induced by injecting 50 μL of 1% formalin in the lip (superficial tissue) and in the temporomandibular joint (TMJ) (deep tissue) of male Wistar rats. The anxiety level was measured by the elevated plus maze (EPM) test. The standard measures (number of entries into open and enclosed arms, and time spent in opened ones), were recorded. The three measures of plus-maze behavior calculated were the percentage of entries into the open arms (% EOA) (100 X open/total), the percentage of time spent in the open arms (% TSOA) (100 X open/total) and the number of entries into the closed arms (NECA). Data were analyzed with ANOVA and Tukey’s tests. Results: The formalin injection in the lip and in the TMJ region significantly increased the anxiety level as measured by the percentage of time spent inside and the number of entries in the open arms of the EPM test, but did not increase the general activity measured by the number of entrances in the closed and opened arms. Anxiety response was significantly reduced by Diazepam® administration (1 mg/kg) before the formalin injection to lip/TMJ. Conclusion: The results suggest that the orofacial nociceptive response induced by the injection of 1% formalin in the lip or TMJ region increases the anxiety level in rats and that Diazepam® can reduce it.

Influence of ethanol and morphine on pain perception evoked by deep tissue injury

The aim of this study was to evaluate the effect of ethanol and morphine on nociceptive behavioral responses evoked by the injection of formalin into the temporomandibular joint region of rats (the TMJ formalin test). In experiment 1, animals were given an ethanol solution (6.5%) or tap water to drink for 4 and 10 days, before the procedure for TMJ pain. In the group treated for 4 days, significant analgesia was observed in the TMJ formalin test, whereas the group treated for 10 days did not show this effect, revealing the development of tolerance to ethanol antinociceptive effects. In experiment 2, animals were submitted to chronic regimen of ethanol (6.5% for 10 days) and the control group was given tap water to drink. After this period, morphine (10 mg/kg i.p.) was administrated 30 minutes before the TMJ formalin test. Morphine had the same analgesic effect in both groups, showing that the treatment with ethanol was not able to alter the analgesic potency of morphine. The results showed that ethanol can affect nociceptive behavioral responses related to pain from deep tissues, like the TMJ, and the absence of interaction between ethanol and morphine suggest that ethanol-induced analgesia was mediated by nonopiate mechanisms.