Painmanagement after oral surgeries is essential to enhance recovery, reduce negative outcomes and improve the experience of the patient.
Naltrexone (NTX) is a non-selective
opioid receptor antagonist that has been shown to modulate neuro-
inflammation when employed in low to ultra-low doses. In addition, ultra-low dose
naltrexone (ULDN) has been shown to potentiate
opioids'
analgesia and to have
opioid-sparing effects. Herein it was investigated the effect of ULDN in a model of postoperative
orofacial pain in rats, and it was tested the hypothesis that blockade of TLR4-signalling pathway contributes to its antinociceptive effect. Systemic NTX reduced heat
hyperalgesia in female rats and heat and
mechanical hyperalgesia in male rats after incision surgery. Combined treatment with NTX and
morphine, both at ineffective doses, resulted in a significant reduction of heat
hyperalgesia in male rats. NTX injection at the incision site failed to change heat
hyperalgesia, but injection at the trigeminal ganglion (TG) or subnucleus caudalis (Sp5C) caused a significant reduction in heat
hyperalgesia. At these sites, blockade of TLR4 impeded NTX effect.
Lipopolysaccharide (LPS) injection in the intraoral mucosa resulted in facial heat
hyperalgesia an increase in IL-1β levels in the TG, which were reduced by systemic NTX. Stimulation of macrophages with LPS resulted in increase of
nitric oxide, IL-1β and CXCL-2 levels which were reduced by NTX. Altogether, these results provide evidence for an antinociceptive effect of ULDN in postoperative
orofacial pain and suggest that blockade of TLR4 and downstream signaling pathway contribute to its effect.