Nerve growth factor-induced muscle hyperalgesia facilitates ischaemic contraction-evoked pain.

Background: Intramuscular injection of Nerve Growth Factor (NGF) may influence the responsiveness of active chemo-sensitive channels affecting muscle pain sensitivity. This double-blinded crossover study in healthy humans assessed contraction-evoked pain responses and pain sensitivity during acute ischaemia in the tibialis anterior (TA) muscle before and 24 hr after five distributed NGF injections (1 µg, 4 cm interval) compared with control injections (isotonic-saline).

Methods: Twenty-one subjects participated in two experimental phases, each including five sessions over 7 days, with a gap of 4 weeks in-between. Muscle pain intensity evoked with daily functional tasks (Likert scale score) was collected using a paper diary. Pain intensity evoked by ischaemic and non-ischaemic contractions numerical rating scale (NRS) was collected at Day0 and Day1. Pressure pain thresholds (PPTs) on the TA were recorded before (Day0), 3 hr, 1, 3, and 7 days post-injection, and after the ischaemic-contractions and post-cuff deflation at Day0 and Day1.

Results: Increased Likert scores of pain were present for 7 days after NGF compared to control injections (p < .05). Higher NRS pain scores of ischaemic-contractions were seen when contracting the muscle injected with NGF compared to baseline (p = .003) and control (p = .012). Pain during non-ischaemic contractions was not significantly affected by NGF injections. Decreased PPTs were found at 3 hr, Day1 and Day3 post-injection (p < .05) in both conditions. Compared with pre-contractions, PPTs were increased following ischaemic contractions at Day0 (p < .05) and Day1 (p < .05) in both conditions.

Conclusion: This study showed that ischaemic contraction-evoked pain was facilitated in an NGF-sensitized muscle.

Significance: Acidification of the muscle environment may affect muscle nociceptors and pain by different mechanisms, including activation of ASIC and TRPV1. In this study, pain evoked following ischaemic contractions was increased in the Nerve Growth Factor (NGF)-sensitized muscle compared with non-ischaemic contractions and in the non-sensitized muscle. These findings illustrate that responses of peripheral afferents under ischaemic conditions are altered by a pre-sensitized muscle. This highlights the role of growth factors, including NGF, in peripheral muscle sensitization with clinical implications for ischaemic myalgia.