Background & Aims
Non-specific low back pain (LBP) affects people of all ages globally, constituting a significant health burden. Adverse Childhood Experiences (ACEs) and stress are established risk factors for chronic low back pain development in humans. Central to this process is the sensitization of dorsal horn neurons (DHNs), a key element contributing to ongoing and evoked chronic LBP. In a preclinical study, repeated restraint stress in adulthood induced latent DHN sensitization, priming them for manifest sensitization upon subsequent NGF injection as mild nociceptive input (1). Our hypothesis posits that stress during adolescence induces long-term DHN sensitization, heightening sensitivity to painful stimuli. Hence, our investigation explores whether adolescent stress acts as a predisposing factor for adult low back pain.
Methods
Male and female Wistar rats during adolescence underwent restraint stress (RS) from post-natal day PD21 to PD32, 1 hour each day. Additionally, social isolation (SI) was imposed on another group from PD21 to PD50, while the control group received regular handling. Upon reaching adulthood, the experimental model of low back pain was induced by administering two injections of NGF/Saline into the lumbar multifidus muscle on PD85 and PD90 (2). The resulting nociceptive deep muscular hyperalgesia was assessed using the Pressure Pain Threshold (PPT), and the cutaneous mechanical hyperalgesia was measured with the Paw Withdrawal Threshold (PWT). Measurements were conducted both before and after the period of stress during adolescence, as well as before and after the injections administered in adulthood.
Results
Adolescent restraint stress had a moderate impact on PPT (pain threshold) in females (Cohen’s d=0.6), while males experienced a significant PPT decrease (p<0.0001) two days after stress. On PD36, both male (p=0.008) and female (p=0.038) PWT (pain withdrawal threshold) were reduced, with persistent significance observed in adult males (p=0.039). In the RS group receiving a saline injection followed by NGF injection, females reported moderate mechanical hyperalgesia (d=0.5) in the lower back, with a more pronounced effect observed in males (d=0.8). Furthermore, post-social isolation (PD 51) resulted in a significant PPT decrease in males (p=0.0362), while females showed a non-significant difference (p > 0.05) between stressed and control groups. Similarly, males exhibited a significant PWT drop post-social isolation (p=0.016), whereas females showed a non-significant difference ( p > 0.05).
Conclusions
Restraint stress induces profound muscular hyperalgesia in both males and females, yet females demonstrate a faster recovery in adulthood. A less intense stress event can result in transient hyperalgesia that does not endure into adulthood. Physical trauma can contribute to the susceptibility of low back pain in both genders. However, chronic low back pain in males may be linked to emotional neglect, whereas females seem to be relatively unaffected by such factors. The findings imply that dorsal horn neurons were sensitized in both males and females due to adolescent stress. However, the test-retest paradigm led to a more robust habituation to these interventions in Wistar rats.
References
(1) Singaravelu, S.K., Goitom, A.D., Graf, A.P., Moerz, H., Schilder, A., Hoheisel, U., Spanagel, R. and Treede, R.D., 2022. Persistent muscle hyperalgesia after adolescent stress is exacerbated by a mild-nociceptive input in adulthood and is associated with microglia activation. Scientific Reports, 12(1), p.18324.
(2)Hoheisel, U., Reuter, R., de Freitas, M.F., Treede, R.D. and Mense, S., 2013. Injection of nerve growth factor into a low back muscle induces long-lasting latent hypersensitivity in rat dorsal horn neurons. PAIN®, 154(10), pp.1953-1960.
Presenting Author
Deepika Singhal
Poster Authors
Topics
- Gender/Sex Differences