Local Kappa Opioid Receptor Activation Decreases Temporomandibular Joint Inflammation

Abstract

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.

Gonadal hormones modulate the responsiveness to local β‐blocker‐induced antinociception in the temporomandibular joint of male and female rats

“…In the TMJ region, gonadal hormones might act on inflammatory and/or resident cells to increase the expression of β‐AR in these cells. Consistent with this idea, TMJ formalin induces inflammatory cell migration (Chicre‐Alcântara et al., ), and β‐AR are expressed in neutrophils, macrophage, eosinophils, mast cell lymphocytes, (Barnes, ) and basophile cells (Perper et al., ). Furthermore, gonadal hormone receptors are known to be expressed in inflammatory cells, as demonstrated by the presence of androgen receptor in macrophages (Fang et al., ), progesterone receptors in T lymphocyte cells (Butts et al., ) and oestradiol receptors in mast cells (Nicovani and Rudolph, ), macrophages (Capellino et al., ) and T‐cells (Tornwall et al., ).…”

Effect of pre-emptive analgesia on clinical parameters and tissue levels of TNF-α and IL-1β in third molar surgery: a triple-blind, randomized, placebo-controlled study

“…Certain mechanisms have been proposed to explain the inflammation that occurs as a result of surgical procedures, but a complete understanding of how these events are fully triggered remains unclear. Proinflammatory cytokines such as TNF-a and interleukin 1 beta (IL-1b) have often been described as important mediators in this process [10][11][12][13] . Experimental studies involving acute pain models suggest that IL-1b sensitizes nociceptors and causes hyperalgesia, therefore working actively in the pathophysiology of this type of pain [14][15][16] .…”

Effects of peripheral κ opioid receptor activation on inflammatory mechanical hyperalgesia in male and female rats

“…However, peripheral KOR effects have been also demonstrated in somatic neuropathic and inflammatory pain models [4,20,24]. More recent studies showed that local KOR activation also decreases temporomandibular joint (TMJ) pain as well as inflammation and prevents the loss of alveolar bone and periodontal tissue [3,7,26,27]. …”