Background & Aims

Cancer patients commonly experience debilitating neuropathic pain that are the result of chemotherapy treatment and cancer metastasis to bone. There are currently no curative treatments for these neuropathies and clinical treatments focus on symptom management. Analgesics such as gabapentinoids, serotonin-norepinephrine reuptake inhibitors, and opioids are used to alleviate these neuropathic pains. However, these analgesics provide only temporary relief that is susceptible to breakthrough pain and have side effect profiles that limit therapeutic windows. The kratom (Mitragyna speciosa) alkaloid mitragynine has previously been shown in mice to alleviate chemotherapy-induced neuropathic pain (CIPN). The kratom alkaloid speciogynine has previously been shown in rats to provide antinociceptive effects. Utilizing C3H/HeJ mice in a paclitaxel CIPN model and an implantation model of cancer-induced bone pain (CIBP), we assessed the potential therapeutic capacity of mitragynine and speciogynine to attenuate pain-related behaviors associated with both neuropathic pain models. Tumor metastasis produced distinct mechanical allodynia but neither cold allodynia nor thermal hyperalgesia. Both mitragynine and speciogynine dose-dependently reduced mechanical allodynia in both CIPN and CIBP models. Elucidation of receptor activity was conducted using pharmacological antagonism studies and findings suggest that opioid, a2 adrenergic, and 5-HT1A receptor agonism underlie the analgesic effects of mitragynine. Analgesic effects of speciogynine were observed to be mediated via opioid and adrenergic activity; serotonergic activity was dispensable. Both mitragynine and speciogynine show promise in alleviating mechanical allodynia associated with both chemotherapy and tumor metastasis to bone. Their poly-pharmacological effects may offer improved therapeutic activity with reduced side effects compared to current treatments.

Funding: This work received support from the Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center startup funding as well as support by the National Institute on Drug Abuse (DA25267 and DA48353) (CRM, LRM, JLW).

Methods

A total of 112 adult male and female C3H/HeJ mice (Jackson Laboratories, Bar Harbor, ME) were used for all experiments.
The fibrosarcoma implantation procedure utilized for this study is previously described (Wacnik et al., 2001). Post-implantation day 13 was utilized as a humane endpoint.
Morphine, clonidine, and buspirone were used as positive controls to assess opioid/ adrenergic/ serotonergic activity of mitragynine and speciogynine. Naltrexone, yohimbine, and WAY-100635 were used as respective antagonists. Both kratom alkaloids were provided by Dr. Christopher McCurdy of the University of Florida’s College of Pharmacy Medicinal Chemistry department.
Mechanical allodynia assessment was completed using the von Frey assay (0.4 – 4.0 g stimulus intensity) utilizing the “up-down” method (Chaplan et al., 1994). Reactive responses of the paw upon filament application was considered a response. Mechanical allodynia assessments were conducted by blinded observers.

Results

Tumor metastasis produced distinct mechanical allodynia. Mitragynine (17.8 – 100 mg/kg, i.p.) significantly (F (1.360, 9.518) = 21.53, p < 0.0001) attenuated CIBP-induced mechanical allodynia. Speciogynine (10 – 32 mg/kg, i.p.) similarly significantly (F (1.277, 8.939) = 21.53, p = 0.0008) attenuated CIBP-induced mechanical allodynia. When either naltrexone, yohimbine, or WAY-100635 were administered prior to mitragynine, antagonism was observed, suggesting opioid, adrenergic, and serotonergic mediation of allodynic attenuation. Similar activity was observed with speciogynine, though WAY-100635 did not antagonize speciogynine-induced anti-allodynia.

Conclusions

In the present study calcaneus NCTC-2472 fibrosarcoma cell implantation into syngeneic C3H/HeJ mice produced mechanical allodynia associated with measurable local tumor growth starting at PID 2 and lasting to the humane endpoint of PID 13.
Both mitragynine and speciogynine were observed to have attenuated mechanical allodynia resulting from simulated fibrosarcoma metastasis. The findings of the pharmacological antagonism studies in the CIPB model are similar to those within the chemotherapy-induced peripheral neuropathy model (Ortiz et al., 2023) and suggest that opioid, ?2 adrenergic, and 5-HT1A receptor agonism is driving the attenuating effects of mitragynine. However, with WAY-100635 failing to antagonize speciogynine, 5-HT1A activity is likely dispensable for speciogynine to attenuate mechanical allodynia in CIBP.
Ultimately, it is presented here that the kratom alkaloids mitragynine and speciogynine may yield potential therapeutic utility for the treatment of CIBP.

References

Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M., & Yaksh, T. L. (1994). Quantitative assessment of tactile allodynia in the rat paw. Journal of Neuroscience Methods, 53(1), 55–63. https://doi.org/10.1016/0165-0270(94)90144-9

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Ortiz, Y. T., Bilbrey, J. A., Felix, J. S., Kienegger, E. A., Mottinelli, M., Mukhopadhyay, S.,
McCurdy, C. R., McMahon, L. R., & Wilkerson, J. L. (2023). Cannabidiol and mitragynine exhibit differential interactive effects in the attenuation of paclitaxel-induced mechanical allodynia, acute antinociception, and schedule-controlled responding in mice. Pharmacological Reports: PR. https://doi.org/10.1007/s43440-023-00498-w

Peters, C. M., Ghilardi, J. R., Keyser, C. P., Kubota, K., Lindsay, T. H., Luger, N. M., Mach, D. B., Schwei, M. J., Sevcik, M. A., & Mantyh, P. W. (2005). Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain. Experimental Neurology, 193(1), 85–100. https://doi.org/10.1016/j.expneurol.2004.11.028

Wacnik, P. W., Eikmeier, L. J., Ruggles, T. R., Ramnaraine, M. L., Walcheck, B. K., Beitz, A. J., & Wilcox, G. L. (2001). Functional Interactions between Tumor and Peripheral Nerve: Morphology, Algogen Identification, and Behavioral Characterization of a New Murine Model of Cancer Pain. The Journal of Neuroscience, 21(23), 9355–9366. https://doi.org/10.1523/JNEUROSCI.21-23-09355.2001

Zaj?czkowska, R., Kocot-K?pska, M., Leppert, W., & Wordliczek, J. (2019). Bone Pain in Cancer Patients: Mechanisms and Current Treatment. International Journal of Molecular Sciences, 20(23), 6047. https://doi.org/10.3390/ijms20236047

Presenting Author

Yuma T. Ortiz

Poster Authors

Yuma Ortiz

PhD

Hodge School of Pharmacy, Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX USA

Lead Author

Sushobhan Mukhopadhyay PhD

College of Pharmacy, Medicinal Chemistry, University of Florida, Gainesville, FL USA

Lead Author

Christopher McCurdy PhD

College of Pharmacy, Medicinal Chemistry, University of Florida, Gainesville, FL USA

Lead Author

Lance McMahon PhD

Hodge School of Pharmacy, Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX USA

Lead Author

Jenny Wilkerson

PhD

Hodge School of Pharmacy, Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX USA

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Cancer Pain & Palliative Care