Subcutaneous Neuromodulation Activates Central Pain-Suppression Pathways for Analgesia.

AIMS: Peripheral neuromodulation, which can be considered a flow of signals from the body to the brain, induces pain relief. However, whether subcutaneous neuromodulation, which regulates specific neural circuits for analgesia, remains largely elusive. This study aimed to evaluate the analgesic effects of subcutaneous mechanical stimulation (SMS) on neuropathic pain. METHODS: A stainless-steel needle (0.5 cm long) was inserted into the subcutaneous tissue. Mechanical allodynia, thermal hyperalgesia, and conditioned place preference (CPP) were assessed in rodent models of localized inflammation of the dorsal root ganglia (LID) and spared nerve injury (SNI). Optogenetic and chemogenetic tools were employed in conjunction with electrophysiological recordings, molecular analyses, and pharmacological interventions to elucidate the underlying mechanisms of SMS-induced analgesia. RESULTS: Subcutaneous needle insertion generated mechanical force, activating Piezo channels. SMS attenuated mechanical allodynia and thermal hyperalgesia and induced CPP in the LID and SNI models. Naloxone pretreatment did not significantly affect SMS-induced analgesia. SMS activated GABAergic neurons in the NAc shell, and their inhibition reversed the SMS effects in LID rats. Furthermore, activation of the IL-to-nucleus accumbens (NAc) shell projections was essential for SMS-induced analgesia and CPP. CONCLUSION: These findings indicate that SMS activates central pain-suppression pathways, providing a potential framework for clinical pain management.