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Painful conditions of the temporomandibular joint (TMJ) are challenging to manage and most attempts often result in unsatisfactory outcomes. In such context, nanocarrier systems, such as polymeric micelles, have been showing encouraging results in solving therapeutic limitations. Poloxamers are widely used, especially PL 407, because of their high biocompatibility and approval by the Food and Drug Administration (FDA) for clinical use. 15-deoxy- Δ12,14 -prostaglandin J 2 (15d-PGJ 2 ) has shown important antinociceptive and anti-inflammatory activity. The present study evaluated the efficacy and viability of the micellar system of PL-15dPGJ 2 in a formalin-induced acute pain model in the temporomandibular joint of rats. The PL-15dPGJ 2 was prepared and characterized. The animals were pretreated with an intra-articular injection of PL-15dPGJ 2 followed by the formalin challenge. The nociceptive response was evaluated at different time-periods and the periarticular tissue and articular wash were collected for analysis. We found that intra-articular injection of PL-15d-PGJ 2 produced pain relief at lower concentrations and in a sustained manner compared with free 15d-PGJ 2 . Moreover, a strong anti-inflammatory effect was observed with decreased levels of key pro-inflammatory cytokines and modulation of the leukocyte migration process. Our findings suggest that 15d-PGJ 2 combined with a poloxamer micellar system provided clinical relevance in terms of bioavailability, long-lasting effect, and safe dosage. The formulation investigated herein is a promising micellar carrier system for managing pain conditions of the TMJ., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors stated explicitly that a patent relating to this study was requested entitled “Pharmaceutical composition of 15-deoxy-delta-(12,14)-prostaglandin J(2) in a poloxamer-based micellar system and its use for treatment of inflammatory conditions” n° WO2016044902-A1., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We examined the effect of the peripheral application of glutamate and capsaicin to the temporomandibular joint (TMJ) in influencing the activation and central sensitization of TMJ-responsive nociceptive neurons in the trigeminal subnucleus caudalis/upper cervical cord (Vc/UCC). The activity of single neurons activated by noxious mechanical stimulation of the TMJ was recorded in the Vc/UCC of 49 halothane-anesthetized male rats. Cutaneous mechanoreceptive field (RF), cutaneous mechanical activation threshold (MAT), and TMJ MAT of each neuron were assessed before and after injection of 0.5 M glutamate (or vehicle) and 1% capsaicin (or vehicle) into the TMJ. A total of 49 nociceptive neurons (37 nociceptive-specific, 12 wide-dynamic-range) that could be activated by blunt noxious mechanical stimulation of the TMJ were studied. When injected alone, glutamate and capsaicin activated and induced central sensitization (reflected in cutaneous RF expansion and cutaneous and/or TMJ MAT reduction) in most Vc/UCC neurons. Following glutamate injection, capsaicin evoked greater activity and less cutaneous/TMJ MAT reduction compared with capsaicin alone, whereas capsaicin abolished all subsequent glutamate-evoked activity and depressed cutaneous RF expansion in most neurons. Glutamate effects on deep afferents and Vc/UCC neurons were analogous since glutamate sensitized afferent and neuronal responses to capsaicin but the desensitizing effects of capsaicin on glutamate-evoked excitability of Vc/UCC neurons contrast with the lack of capsaicin-induced modulation of glutamate-evoked afferent excitability [Lam, D.K., Sessle, B.J., Hu, J.W., 2008a. Glutamate and capsaicin effects on trigeminal nociception I: activation and peripheral sensitization of deep craniofacial nociceptive afferents. Brain Res. doi:10.1016/j.brainres.2008.11.029], suggesting that peripheral and central sensitization may be differentially involved in the nociceptive effects of glutamate and capsaicin applied to deep craniofacial tissues.

We have previously documented that peripheral N-methyl-d-aspartate (NMDA) receptor mechanisms are involved in nociceptive reflex increases in jaw muscle activity to injection of mustard oil or glutamate into the rat temporomandibular joint (TMJ). The aim of the present study was to determine whether peripheral NMDA receptor mechanisms are also involved in the nociceptive reflex responses in the jaw muscles evoked by injection of the inflammatory irritant and algesic chemical capsaicin into the TMJ. The effects of peripheral injection of NMDA receptor antagonists, MK-801 and APV, on the increases in electromyographic (EMG) activities of digastric and masseter muscles reflexly evoked by capsaicin injection into the TMJ were tested in halothane-anesthetized male rats. The capsaicin injection following pre-injection of vehicle evoked significant increases in EMG activity in both digastric and masseter muscles whereas pre-injection of MK-801 or APV into the TMJ resulted in a significant concentration-related reduction in the magnitude of capsaicin-evoked digastric and masseter EMG activity (ANOVA-on-ranks, P < 0.05). This finding indicates that capsaicin-evoked digastric and masseter EMG activity can be attenuated by pre-injection into the TMJ of NMDA receptor antagonists, and that the activation of peripheral NMDA receptors may be important in the mechanisms whereby capsaicin evokes nociceptive trigeminal responses.

This study sought to assess sleep patterns in rats injected with Freund's adjuvant (FA) in the temporomandibular joint (TMJ) as a potential experimental orofacial pain model. Pain response to indomethacin was also assessed. Rats were implanted with electrodes to record electrocorticogram and eletromyogram signals. After a baseline (B) recording, they were injected with Freund's adjuvant (orofacial pain group, n=8) or saline (sham group, n=8) in the temporomandibular joint, and their sleep was monitored over two 12-h light periods. In the second phase of the study, after injecting Freund's adjuvant, indomethacin was administered (1 mg/kg p.o.) at 12- intervals, and sleep patterns were recorded for two additional light periods. The orofacial pain group showed a reduction in sleep efficiency during the two light periods compared with the baseline recording and with the sham group (p<0.001). Increases in sleep and paradoxical sleep (PS) latencies of approximately 200% and 420%, respectively, were observed, as well as an increase in the number of awakenings during both periods (p<0.001). Treatment with indomethacin increased sleep efficiency (p<0.001) and paradoxical sleep time (p<0.001). The number of awakenings (p<0.001) and sleep (p<0.001) and paradoxical sleep latencies (p<0.001) were reduced reestablishing the normal sleep pattern. The results showed the reliability and usefulness of the temporomandibular joint pain model to characterize sleep disturbances related to pain and its response to indomethacin.

Injection of glutamate into the rat temporomandibular joint (TMJ) evoked a concentration-dependent increase in jaw muscle activity. We investigated whether there are sex-related differences in glutamate-evoked jaw muscle activity that are mediated by sex hormones and whether prior injection of glutamate into the TMJ alters the magnitude of jaw muscle activity evoked by a subsequent injection of the algesic and inflammatory compound mustard oil (MO) into the TMJ. The magnitude of glutamate-evoked digastric and masseter muscle activity was significantly greater in female than male rats when 1000 mM glutamate was injected into the TMJ. Gonadectomy significantly reduced the magnitude of glutamate-evoked digastric muscle activity in female rats. Treatment of gonadectomized female rats with estrogen (20 microg/day) increased the magnitude of glutamate-evoked digastric muscle activity. Glutamate-evoked jaw muscle activity in gonadectomized and estrogen-treated gonadectomized males was not significantly different from intact males. Prior injection of glutamate over a concentration range of 10-1000 mM significantly increased digastric muscle activity evoked by MO injection into the TMJ 30 min later. In contrast, MO-evoked masseter muscle activity was significantly increased by prior injection of 250 mM glutamate only. There were, however, no sex-related differences in the enhancement of MO-evoked jaw muscle activity by prior injection of glutamate. These findings indicate that there are sex-related differences in glutamate-evoked jaw muscle activity that are dependent on female sex hormones, and increased glutamate concentrations sensitize the TMJ to noxious chemical stimuli.

The effect of intrathecal administration of the 5-HT(3) receptor agonist 2-methyl-5-hydroxytryptamine (2m-5HT) on jaw muscle activity evoked by mustard oil (MO) injection into the temporomandibular joint of anesthetized rats was examined. One microgram or 100 microg of 2m-5HT significantly enhanced or suppressed jaw muscle responses, respectively. Pre-administration of tropisetron, a 5-HT(3) receptor antagonist, attenuated the effect of 2m-5HT. These results indicate that activation of 5-HT(3) receptors can modulate trigeminal nociceptive responses.

The injection of the small-fibre excitant and inflammatory irritant mustard oil (MO) into the temporomandibular joint (TMJ) region of rats evokes a sustained and reversible increase in electromyographic (EMG) activity of jaw muscles. The 'rekindling' of this nociceptive reflex by intrathecal (i.t.) administration of the opiate antagonist naloxone and mu but not delta and kappa selective opioid antagonist, suggests that it may be modulated by endogenous opioid inhibitory mechanisms.

The effect of intrathecal administration of the GABA(A) receptor antagonist bicuculline methylbromide on jaw muscle electromyographic (EMG) activity evoked by mustard oil injection into the rat temporomandibular joint was studied. Bicuculline given prior to mustard oil augmented the EMG activity evoked by mustard oil, and "rekindling" of EMG activity was induced by bicuculline given 30 min after mustard oil. These results suggest that central GABA(A) receptors modulate reflex responses to noxious craniofacial stimuli.