Supplementary materials SupTab. 1 List of abbreviations of different groups of substances used in experiments with their structure characteristics and effect in neuropathic pain model.

Abbreviation Explanation structure characteristics Effect in neuropathic pain (CCI model)

ENDOGENOUS OPIOID

POMC prohormone of opioid (β-endorphin) and nonopioid peptides (α-MSH) ACTH adrenocorticotropic POMC-derived nonopioid pronocicpetive hormone CLIP corticotropin-like POMC-derived nonopioid peptide pronociceptive intermediate lobe peptide ACTH fragment 18-39

-MSH alpha-melanocyte- POMC-derived nonopioid peptide pronociceptive stimulating hormone ACTH fragment 1-13 -MSH gamma-melanocyte- POMC-derived nonopioid peptide pro- or antinociceptive stimulating hormone POMC fragment 77-87 depending on the dose PENK proenkephalin Prohormone of opioid (enkephalins) and nonopioid peptides (SPQ) Met- -enkephalin PENK-derived opioid peptide antinociceptive enkephalin Tyr-Gly-Gly-Phe-Met BAM22 bovine adrenal medullary PENK-derived opioid peptide antinociceptive peptide 22 Tyr-Gly-Gly-Phe-Met-Arg-Arg-Val-Gly- Arg-Pro-Glu-Trp-Trp-Met-Asp-Tyr-Gln- Lys-Arg-Tyr-Gly BAM8-22 bovine adrenal medullary PENK-derived nonopioid peptide antinociceptive peptide 8-22 Val-Gly-Arg-Pro-Glu-Trp-Trp-Met-Asp- Tyr-Gln-Lys-Arg-Tyr-Gly Peptide E --- PENK-derived opioid peptide antinociceptive Met- and Leu-enkephalin fragment on N- and C-terminus FAE peptides synthesized by us PENK-derived nonopioid peptide pronociceptive in low for these experiments H-Phe-Ala-Glu-Ser-Leu-Pro-Ser-Asp- doses and antinociceptive Glu-Glu-Gly-Glu-Ser-Tyr-Ser-Lys-Glu- in higher Val-Pro-Glu-Met-Glu-OH VGR peptides synthesized by us PENK-derived nonopioid peptide pronociceptive in low for these experiments BAM fragment 8-18 doses and antinociceptive H-Val-Gly-Arg-Pro-Glu-Trp-Trp-Met- in higher Asp-Tyr-Gln-OH SPQ peptides synthesized by us PENK-derived nonopioid peptide pronociceptive for these experiments H-Ser-Pro-Gln-Leu-Glu-Asp-Glu-Ala- Lys-Glu-Leu-Gln-OH PDYN prodynorphin Prohormone of opioid (dynorphin) and nonopioid peptides (des-Tyr-dynorphin) des-Tyr- des-Tyrosine-dynorphin PDYN-derived nonopioid peptide pronociceptive dynorphin

RECEPTORS

DOP -opioid peptide receptor -induced antinociception MOP -opioid peptide receptor opioid receptor agonist-induced antinociception MC4 receptor melanocortin receptor agonist-induced type 4 nociception MC3 melanocortin receptor melanocortin receptor no effect type 3

BIFUNCTIONAL HYBRIDS

OP opioid OP-linker- hybrids composed of two opioid receptor agonist-linker-MC4 MC4 pharmacophores UW1 parent peptide opioid receptor agonist pharmacophore weak antinociception in Tyr-D-Ala-Gly-Phe-NH2 neuropathic pain SHU-9119 parent peptide MC4,3 receptor antagonist weak antinociception in pharmacophore neuropathic pain UW3 Hybrid OP-linker-MC4 Tyr1-D-Ala2-Gly3-Phe4-Ahx5-Nle6- potent antinociception in designed and synthesized cyclo[Asp7-His8-D-Nal(2’)9-Arg10-Trp11- neuropathic pain 12 by us to test / support the Lys ]-NH2 hypothesis UW5 Hybrid OP-linker-MC4 Tyr1-D-Ala2-Gly3-Phe4-Ahx5-Ahx6-Nle7- potent antinociception in designed and synthesized cyclo[Asp8-His9-D-Nal(2’)10-Arg11-Trp12- neuropathic pain 13 by us to test / support the Lys ]-NH2 hypothesis

SupFig.1 Dose-dependent antinociceptive effects of intrathecal (i.t.) administration of Met-enkephalin (A), Peptide E (B), BAM22 (C), and BAM8-22 (D) measured by the von Frey and cold plate tests 15 min after administration in CCI- exposed rats (6-10 animals per group) were normalized and are expressed as the %MPE (mean ± SEM). Intergroup differences were analyzed using one-way ANOVA followed by Bonferroni's multiple comparisons test. *p < 0.05, **p < 0.01, ***p < 0.001 vs vehicle (V)-treated CCI-exposed rats.