A DNA-Grounded Map of 27 Non-Opioid Analgesic Targets

From sequence alone: one read per gene (γ), three levers, every clinical magnitude open [O].

A single jamming-lattice read — Layer-1 γ, a nearest-neighbour stacking-energy read of the promoter (SantaLucia 1998) — is taken for 27 nociception genes and mapped onto the R19 firing-threshold scale, |hsp| = (2/3√3) γ1.5. The reads are bit-reproducible (corr(γ,GC) = 0.99898 over the full set, drift 0, offline). γ reads promoter switch-threshold structure only; it is never equated with any channel voltage, potency, dose, in-vivo selectivity, or clinical effect — all of which are graded [O]. The map sorts the targets into three levers (reduce inward current, increase outward current, remove the sensitising drive), ranks them by burden, and adds a precision local-anaesthesia map — each target on its own page.

41 pages · 27 target reads · 11/11 reproducibility gates, drift 0, offline · CC BY 4.0. Every page is self-contained and answer-first; every clinical magnitude is [O] (open). This is a free, public-benefit, proposal-only hypothesis.

Map contents

  1. §0 · How to read this map One DNA read per gene, three levers, the firewall, and the grading legend.
  2. §L1 · Lever 1 — reduce the inward current Reduce the inward (depolarising) current to raise the firing threshold.
  3. CACNA1H — CaV3.2 γ 1.6357 · |hsp| 0.8052 · read [V], clinical [O].
  4. CACNA1B — CaV2.2 γ 1.596 · |hsp| 0.776064 · read [V], clinical [O].
  5. ASIC1 — ASIC1 γ 1.5161 · |hsp| 0.718522 · read [V], clinical [O].
  6. ASIC3 — ASIC3 γ 1.4818 · |hsp| 0.694277 · read [V], clinical [O].
  7. TRPV1 — TRPV1 γ 1.456 · |hsp| 0.676223 · read [V], clinical [O].
  8. P2RX3 — P2X3 γ 1.4421 · |hsp| 0.666563 · read [V], clinical [O].
  9. SCN9A — NaV1.7 γ 1.4014 · |hsp| 0.638545 · read [V], clinical [O].
  10. SCN11A — NaV1.9 γ 1.3952 · |hsp| 0.634312 · read [V], clinical [O].
  11. SCN10A — NaV1.8 γ 1.3136 · |hsp| 0.579486 · read [V], clinical [O].
  12. TRPM8 — TRPM8 γ 1.2719 · |hsp| 0.552112 · read [V], clinical [O].
  13. SCN3A — NaV1.3 γ 1.2645 · |hsp| 0.547301 · read [V], clinical [O].
  14. TRPA1 — TRPA1 γ 1.2297 · |hsp| 0.524864 · read [V], clinical [O].
  15. CACNA2D1 (adjacent) — alpha2delta-1 (CaV auxiliary subunit) γ 1.4414 · |hsp| 0.666078 · read [V], clinical [O].
  16. §L2 · Lever 2 — increase the outward K⁺ current Increase the outward K⁺ (M-current) brake to restore the OFF basin.
  17. KCNQ2 — KV7.2 γ 1.5768 · |hsp| 0.762102 · read [V], clinical [O].
  18. KCNQ5 — KV7.5 γ 1.5307 · |hsp| 0.728926 · read [V], clinical [O].
  19. KCNQ3 — KV7.3 γ 1.498 · |hsp| 0.705693 · read [V], clinical [O].
  20. §L3 · Lever 3 — remove the sensitising drive Remove the upstream sensitising drive (growth-factor and CGRP signalling).
  21. CALCB — beta-CGRP (ligand) γ 1.5169 · |hsp| 0.71909 · read [V], clinical [O].
  22. NTRK1 — TrkA (NGF receptor) γ 1.5036 · |hsp| 0.709654 · read [V], clinical [O].
  23. CALCA — alpha-CGRP (ligand) γ 1.4876 · |hsp| 0.698357 · read [V], clinical [O].
  24. NGF — NGF (nerve growth factor, ligand) γ 1.4688 · |hsp| 0.68516 · read [V], clinical [O].
  25. RAMP1 — RAMP1 (receptor-activity-modifying protein 1) γ 1.4249 · |hsp| 0.654673 · read [V], clinical [O].
  26. CALCRL — CALCRL (calcitonin-receptor-like receptor) γ 1.2122 · |hsp| 0.5137 · read [V], clinical [O].
  27. §M · Master switch — nociceptor identity PRDM12, the developmental identity switch of the nociceptor lineage.
  28. PRDM12 — PRDM12 (transcription factor) γ 1.5955 · |hsp| 0.775699 · read [V], clinical [O].
  29. §C · Context comparators — routed away from reward Opioid and cannabinoid receptors, listed only as comparators.
  30. OPRD1 — delta-opioid receptor γ 1.476 · |hsp| 0.690204 · read [V], clinical [O].
  31. OPRK1 — kappa-opioid receptor γ 1.4351 · |hsp| 0.661716 · read [V], clinical [O].
  32. CNR2 — CB2 cannabinoid receptor γ 1.3698 · |hsp| 0.617069 · read [V], clinical [O].
  33. OPRM1 — mu-opioid receptor γ 1.2548 · |hsp| 0.541016 · read [V], clinical [O].
  34. §P · Burden-weighted target prioritisation Targets ranked by burden, unmet need, and druggability — never by their map place.
  35. §PB · Precision local anaesthesia A pain-selective differential block: a nociceptor-selective entry port × a charged threshold raiser.
  36. §Pr · Proposals (P1–P6) Six directional proposals that follow from the map — hypotheses to test, not results.
  37. §Fx · Falsification The observation that would refute each proposal; a map that cannot be wrong is not science.
  38. §G · Grading and honesty Three grades [V]/[F]/[O], a fail-closed claim scanner, an L3-honesty gate, and an open ledger.
  39. §RX · For pharmaceutical companies and researchers Free reuse under CC BY 4.0 (including commercial) to broaden the search for non-opioid analgesics.
  40. §Pub · For patients and the public Plain language: a research map, shared free; not a medicine and not medical advice.

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Mesh projected from registry/seam_edges.csv · machine-readable at seams.json