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Background: Temporomandibular disorder (TMD) is a common condition that frequently transitions to chronic symptoms. Experimental pain models that mimic the symptoms of clinical TMD may be useful in understanding the mechanisms, and sex differences, present in this disorder. Here we aimed to comprehensively characterise the nature and time-course of pain, functional impairment and hyperalgesia induced by repeated intramuscular injection of nerve growth factor (NGF) into the masseter muscle, and to investigate sex differences in the NGF-induced pain experience. Methods: 94 healthy individuals participated in a longitudinal observational study with 30-day follow-up. NGF was injected into the right masseter muscle on Day 0 and Day 2. Participants attended laboratory sessions to assess pain (Numerical Rating Scale; NRS), functional limitation (mouth opening distance, Jaw Functional Limitation Scale; JFLS) and mechanical sensitization (pressure pain thresholds; PPTs) on Days 0, 2 and 5 and completed twice daily electronic pain dairies from Day 0 to day 30. Results: Peak pain averaged 2.0/10 (95 % CI: 1.6-2.4) at rest and 4.3/10 (95 % CI: 3.9-4.8) on chewing. Pain-free mouth opening distance reduced from 5.0 cm (95 % CI: 4.8-5.1 cm) on Day 0 to 3.7 cm (95 % CI: 3.5-3.9 cm) on Day 5. The greatest reduction in PPTs was observed over the masseter muscle. Females experienced higher pain, greater functional impairment, and greater sensitivity to mechanical stimuli than males. Conclusion: Intramuscular injection of NGF is a useful model with which to explore the mechanisms, and sex differences, present in clinical TMD.

Many pain biomarkers fail to move from discovery to clinical application, attributed to poor reliability and feasible classifications of at-risk individuals. Preliminary evidence has shown that higher pain sensitivity is associated with slow peak alpha frequency (PAF) and depression of corticomotor excitability (CME). The present study evaluated the reliability of these measures, specifically whether, over several days of pain, a) PAF remains stable and b) individuals show two stable and distinct CME responses: facilitation and depression. Seventy-five healthy participants were given an injection of nerve growth factor (NGF) into the right masseter muscle on Day 0 and Day 2, inducing sustained pain. Electroencephalography (EEG) to assess PAF and transcranial magnetic stimulation (TMS) to assess CME were recorded on Day 0, Day 2 and Day 5. PAF reliability was in the excellent range even without standard pre-processing and ~2 minutes recording length. Moreover, two distinct and stable CME responses were demonstrated: facilitation and depression. These findings support the notion that PAF is a stable trait characteristic, with reliability unaffected by pain, and excellent reliability achievable with minimal pre-processing and ~2 minutes recording, making it a readily translatable biomarker. Furthermore, the study showed novel evidence of two stable corticomotor adaptations to sustained pain. Overall, the study provides support for the reliability of PAF and CME as prospective cortical biomarkers