TRPV1 and TRPV1-Expressing Nociceptors Mediate Orofacial Pain Behaviors in a Mouse Model of Orthodontic Tooth Movement

Abstract

Orthodontic force produces mechanical irritation and inflammation in the periodontium, which is inevitably accompanied by pain. Despite its prevalence, treatment of orthodontic pain is ineffective. Elucidating underlying neural mechanisms is critical to improving the management of orthodontic pain. We have assessed the contribution of transient receptor potential vanilloid subtype 1 (TRPV1) and the TRPV1-expressing subset of nociceptive afferents to pain behaviors induced by orthodontic force in mice. Microfocus X-ray computed tomography analysis showed that application of an orthodontic force of 10 g to the maxillary first molar produced reliable tooth movement in mice. Mouse grimace scale (MGS) was evaluated as an indication of non-evoked spontaneous pain and bite force (BF) was measured for assessing bite-evoked nocifensive behaviors. Orthodontic force increased MGS and decreased BF, both of which were interpreted as increased levels of pain. These behaviors peaked at 1d and returned near to the sham level at 7d. Retrograde labeling and immunohistochemical assays showed TRPV1-expressing peptidergic afferents are abundantly projected to the periodontium. Direct injection of resiniferatoxin into trigeminal ganglia (TG) decreased TRPV1-expressing afferents by half in the targeted region of TG. The chemical ablation of TRPV1-expressing afferents significantly attenuated orthodontic pain behaviors assessed by MGS and BF. Consistently, the knockout of TRPV1 also attenuated orthodontic force-induced changes in MGS and BF. These results suggest that TRPV1 and TRPV1-expressing trigeminal nociceptors constitute a primary pathway mediating orthodontic pain behaviors in mice. This model will be useful for mechanistic studies on orthodontic pain aimed at developing novel approaches for painless orthodontics.

The Utility of Grimace Scales for Practical Pain Assessment in Laboratory Animals

“…In rats, limited studies were carried out into sex differences but no differences were found in the original validation study [ 21 ], or in a later study [ 70 ]. Unfortunately, it appears that most grimace studies in rats and mice appear to have been conducted in one sex, with a large proportion using male animals, see e.g., [ 52 , 71 , 72 , 73 ]. This bias in study design toward males, coupled with the enhanced understanding of the existence of different pathways and immune-cell types for pain processing between male and female rodents [ 74 ], renders extrapolation of findings to female rodents problematic.…”

Local delivery of simvastatin maintains tooth anchorage during mechanical tooth moving via anti‐inflammation property and AMPK/MAPK/NF‐kB inhibition

“…Our group also found that AMPK‐α1 knockout (AMPK‐α1 ‐/‐ ) mice presented larger inflammatory periodontal bone defects and expressed higher levels of inflammatory cytokines than wild‐type (WT) mice 23 . Interestingly, OTM is a biomechanical process accompanied by tension side bone regeneration and pressure side bone resorption, which indicates the AMPK activation in the inflammation‐mediated osteogenesis under biomechanical irritation 24 …”

“…23 Interestingly, OTM is a biomechanical process accompanied by tension side bone regeneration and pressure side bone resorption, which indicates the AMPK activation in the inflammation-mediated osteogenesis under biomechanical irritation. 24 Current in vitro observations grounded on the static-culturing periodontal ligament cells (PDLCs), which led to big inconsistency from the actual stress state of the PDLCs during OTM. In this study, we focused on the anti-inflammation effect of SMV on tensile side of the orthodontic moving tooth in a rodent model.…”

The Utility of Grimace Scales for Practical Pain Assessment in Laboratory Animals

“…Unfortunately, it appears that most grimace studies in rats and mice appear to have been conducted in one sex, with a large proportion using male animals see eg. 52,[71][72][73] . This bias in study design towards males, coupled with the enhanced understanding of the existence of different pathways and immune-cell types for pain processing between male and female rodents 74 , renders extrapolation of findings to female rodents problematic.…”