Presented at the 2013 AAPM Annual Meeting « Back

Neonatal Pain and Neuro-Psychiatric Disorders: Honokiol for Treatment and Prevention

Anna Woodbury, MD LAc, awoodbu@emory.edu¹, Shan Ping Yu¹, Paul Garcia, MD PhD², Ling Wei¹, (1) Emory University, Atlanta, Georgia, (2) Emory University/Atlanta VAMC, Atlanta, Georgia

Introduction: Early pain experiences result in long-term detrimental consequences, yet early opioid exposure leads to numerous undesirable side effects as well. We recently showed that neonatal inflammatory pain causes central neuronal cell death and has long-term deleterious effects. Meanwhile, increasing attention has been given to consequences of early anesthetic exposure in the pediatric population. Honokiol is a naturally-occurring lignan with neurotrophic and analgesic effects. Its proposed mechanism of action is multifactorial, including blocking NMDA receptors and inflammatory pain, increasing the 5HT/5-HIAA ratio, and GABA-A modulation. We hypothesize that honokiol could help optimize pediatric pain management, enhancing analgesia and attenuating insults on the developing brain produced by pain or repeated anesthetic exposure. Materials and Methods: Neonatal rat pups underwent paw-lick testing following injection with intraplantar formalin and either i.p. honokiol treatment or corn oil vehicle control. Pups underwent evaluation for delayed stress and pain responses via behavioral and cytochemical tests. Results: Honokiol significantly decreased recuperation time following formalin injection in the paw-lick test and decreased signs of thermal hyperalgesia in hot plate testing (p<0.05). Honokiol did not show a significant effect on open field testing or defensive withdrawal. Sixteen days after induction of inflammatory pain, the thalamus and hippocampus of honokiol-treated rats showed significantly increased neurogenesis, decreased cell death, and decreased microglia relative to controls (p<0.05). Conclusions: Honokiol prevents pain-induced neuronal death, increases neurogenesis, decreases brain inflammation, and prevents pain sensation and stress-related behavioral responses. References: 1) Mohamad O, et al. Erythropoietin reduces neuronal cell death and hyperalgesia induced by peripheral inflammatory pain in neonatal rats. Mol Pain 2011, 7(51): 1-15. 2) Anand KJ, et al. Tolerance and withdrawal from prolonged opioid use in critically ill children. Pediatrics 2010, 125(5): e1208-1225. 3) Lin YR et al. Effects of honokiol and magnolol on acute and inflammatory pain models in mice. Life Sci 2007, 81: 1071-1078. 4) Mitchell A, Boss BJ. Adverse effects of pain on the nervous systems of newborns and young children: a review of the literature. J Neurosci Nurs 2002, 34(5):228-236. 5) Qun X et al. Antidepressant-like effects of the mixture of honokiol and magnolol from the barks of Magnolia officinalis in stressed rodents. Prog Neuro-Psychoph 2008, 32: 715-725. 6) McNally L et al. Inflammation, glutamate, and glia in depression: a literature review. CNS Spectr 2008, 13(6): 501-510. 7) Zhuo M, Gebhart GF. Effects of neonatal capsaicin treatment on descending modulation of spinal nociception from the rostral, medial medulla in adult rat. Brain Res 1994, 645(1-2):164-178. 8) Lin YR et al. Antinociceptive actions of honokiol and magnolol on glutamatergic and inflammatory pain. J Biom Sci 2009, 16(94): 1-10. 9) Fukuyama Y, et al. Neurotrophic activity of honokiol on the cultures of fetal rat cortical neurons. Bioorg & Med Chem Lett 2002, 12: 1163-1166.

Funding: This work was supported by research grants NS062097 (LW), NS075338 (LW), NS057255 (SPY), FAER (AW), the Gertie Marx Research and Education Award (AW), and AHA EIA award (LW).

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