Isobolographic analysis reveals antinociceptive synergism between Phα1β recombinant toxin and morphine in a model of cancer pain in C57BL/6J mice

Abstract

Background: Phoneutria nigriventer venom contains Phα1β. This toxin and its recombinant form have a remarkable analgesic potential that is associated with blockage of voltage-gated calcium channels and TRPA1 receptors. Although morphine is a mainstay drug to treat moderate and severe pain related to cancer, it has serious and dose-limiting side effects. Combining recombinant Phα1β and morphine to treat pain is an interesting approach that has been gaining attention. Therefore, a quantitative and reliable method to establish the strength of the antinociceptive interaction between these two substances is necessary. The present study was designed to investigate the nature of the functional antinociceptive (analgesic) interaction between Phα1β recombinant toxin and morphine in a model of cancer pain. Methods: Melanoma was produced by intraplantar inoculation of B16-F10 cells into the right paw of C57BL/6J mice. Von Frey filaments measured the paw-withdrawal threshold after intrathecal administration of morphine, recombinant Phα1β, and their combination. Thermal hyperalgesia was assessed using Hargreaves apparatus. The degree of interaction was evaluated using isobolographic analysis. Spontaneous and forced motor performance was assessed with the open-field and rotarod tests, respectively. Results: Co-administration of recombinant Phα1β and morphine synergistically reverses the melanoma-induced mechanical hyperalgesia. The potency of the mixture, measured as the effective dose to reach 50% of maximum possible effect (MPE) in ameliorating mechanical hyperalgesia, was about twice fold higher than expected if the interaction between morphine and recombinant Phα1β was merely additive. Treatment with the combination at doses necessary to reach 50% of MPE caused no spontaneous nor forced motor alterations. Conclusion: The combinatorial use of recombinant Phα1β and morphine allows significant and effective dose reduction of both agents, which has translational potential for opioid-sparing approaches in pain management related to cancer.

PnPP-15, a Synthetic Peptide Derived from a Toxin from Phoneutria nigriventer Spider Venom, Alleviates Diabetic Neuropathic Pain and Acts Synergistically with Pregabalin in Mice

“…Least squares linear regression analysis of the log dose–response curves for PnPP-15 and PGB supplied the calculation of the dose that produced 50% of antinociception [ 37 , 38 ]. PnPP-15 and PGB dose pairs were derived from the ED 50 values of the individual drugs.…”

“…A priori, the animals performed three acclimatization runs for three consecutive days. Only naive animals were used to exclude the possibility of biases related to motor function deficits associated with diabetes [ 37 , 39 ]. The median of the 3 tests represents each parameter for each animal.…”

From the PnTx2-6 Toxin to the PnPP-19 Engineered Peptide: Therapeutic Potential in Erectile Dysfunction, Nociception, and Glaucoma

“…Gomez and C. Castro-Junior (Faculdade Santa Casa de Belo Horizonte, Brazil), especially the toxin named Ph-α-1ß. This toxin interacts with different Ca 2+ channels and shows efficacy in many models of nociception, such as in cancer, fibromyalgia, pancreatitis, postoperative pain, diabetic neuropathic pain, and orofacial pain ( Da Silva Junior et al, 2020 ; Rita Pereira et al, 2020 ; Tonello et al, 2020 ; Aoki et al, 2021 ; Garcia Mendes et al, 2021 ). Another fraction from the venom of P. nigriventer , called PhTx4 ( Figure 1 ) was described having several insect toxins (for review see De Lima et al, 2016 ; Peigneur et al, 2018 ) targeting mainly Na + channels of insects ( De Lima et al, 2002 ; De Lima et al, 2007 ).…”