Analgesic target logic for visceral pain (inherited): a DNA-grounded 27-target firing-threshold map sorted into three drug-class levers

This section inherits a sibling whitepaper — analgesic_threshold_logic v2.0 (DOI 10.5281/zenodo.20733420), a DNA-grounded map of 27 non-opioid analgesic targets — and applies it to digestive visceral pain. Each pain gene's promoter γ sits on the R19 firing-threshold scale |h_sp| = spinodal(γ), which is this package's own §18 afferent spinodal (all 27 reads re-derive bit-for-bit). The targets sort into three drug-class levers — reduce the inward current, open the K_V7 brake, remove the NGF/CGRP drive — and each raises the §18 firing threshold, lowering the gain. The map points each visceral-pain disorder (IBS, functional abdominal pain, biliary colic) to a lever and a cited validated drug class; efficacy, dose, and the felt pain stay [O] / mind (firewall).

This section inherits a sibling whitepaper, analgesic_threshold_logic v2.0 (concept DOI 10.5281/zenodo.20733420, CC BY 4.0 — a reproducible, DNA-grounded map of 27 non-opioid analgesic targets), and applies it to digestive visceral pain on the shared substrate. The inherited engine reads each pain gene's human promoter and returns γ = −mean(NN stacking ΔG, SantaLucia 1998), placing it on the R19 double-well firing-threshold scale |h_sp| = 2(g/3)^1.5 = (2/3√3)γ^1.5 — which is identically this package's inherited/vp_substrate.spinodal, so re-deriving all 27 target reads through the local substrate reproduces the inherited firing thresholds bit-for-bit (max |h_sp| and barrier drift zero), and that firing-threshold axis IS the §18 visceral-afferent spinodal the gain χ = 1/k diverges at — the identity that makes the inheritance principled rather than a paste. The 27 targets sort into three intervention levers, all raising the same firing threshold from different directions: L1 reduce the inward (excitatory) current (block depolarising Na_V / Ca_V / ASIC / P2X / TRP channels), L2 increase the outward K+ current (open K_V7), L3 remove the up-stream NGF / CGRP sensitising drive; twenty of the twenty-seven are expressed on the gut visceral afferent. Read on the §18 afferent, the three levers do one thing: for a sensitised afferent (visceral hypersensitivity) each lever, applied at increasing structural strength δ (a fraction of the sensitisation removed, never a dose), raises the firing threshold T = spinodal − b_eff and lowers the gain χ = 1/k monotonically back toward the baseline 1/(2g), making the inherited map a drug-class pointer for every digestive visceral-pain disorder — IBS hypersensitivity, functional abdominal pain, functional-dyspepsia pain, biliary colic, oesophageal-spasm pain — naming which lever and which cited validated agent class realises it (the αδ-1 gabapentinoid class and the emerging Na_V1.8 / P2X3 nociceptor-selective classes for L1, K_V7 openers for L2, anti-NGF / anti-CGRP for L3). A burden-weighted prioritisation of the GI nociceptor targets (inherited declared weights B/U/D over cited 1–5 tiers, with γ / |h_sp| never folded into the clinical score) re-derives the inherited score exactly and surfaces the realised peripheral case first (Na_V1.8, then NGF, then Na_V1.7), and a precision pain-selective visceral local-anaesthesia map pairs the four gut nociceptor entry ports with a charged firing-threshold raiser. The firewall is inherited verbatim and non-negotiable: γ reads promoter switch-threshold STRUCTURE only — it is never a channel activation voltage, a drug potency, a dose, an in-vivo selectivity, or a clinical effect; every such magnitude, the differential-block ratio, and absolute efficacy are [O]; the lever strength δ is structural, not a dose; the L3 mechanism link is [O] cited biology; and the felt / affective pain is mind's (this layer moves only the peripheral afferent-gain term, the §27 firewall kept). No molecule is designed, no synthesis or dose is given, and nothing here diagnoses, treats, or prescribes — it is a proposal-only target hypothesis. The drift-zero inheritance and the three-lever de-sensitisation of the §18 afferent and the burden re-derivation are [V] / [F]; every clinical magnitude (potency, dose, in-vivo selectivity, differential-block ratio, efficacy) and the felt pain (mind) are [O] with stated obstacles.

Every visceral-pain reading in this volume — the §18 IBS hypersensitivity and functional abdominal pain, the §17 functional-dyspepsia pain, the §25 biliary colic, the §16 oesophageal-spasm pain — ends at the same question: which intervention raises the visceral afferent's firing threshold, and toward which drug class does the mechanism point. This section answers it by inheriting a sibling whitepaper, analgesic_threshold_logic v2.0 (DOI 10.5281/zenodo.20733420, CC BY 4.0): a reproducible, DNA-grounded map of 27 non-opioid analgesic targets. It is not a paste — it is the same substrate read a second way.

The map's engine reads each pain gene's human promoter and returns γ = −mean(NN stacking ΔG, SantaLucia 1998), then places γ on the R19 double-well firing-threshold scale |h_sp| = 2(g/3)^1.5 = (2/3√3)γ^1.5. That scale is this package's own inherited/vp_substrate.spinodal: re-deriving all 27 reads through it reproduces the inherited firing thresholds bit-for-bit (max |h_sp| drift 0e+00, max barrier drift 0e+00 — drift zero). The analgesic firing-threshold axis is the §18 visceral-afferent spinodal the gain χ = 1/k diverges at; that identity is why the inheritance is principled.

The 27 targets sort into three intervention levers, all raising the same firing threshold from different directions: L1 reduce the inward (excitatory) current (block depolarising Na_V / Ca_V / ASIC / P2X / TRP channels), L2 increase the outward K⁺ current (open K_V7), L3 remove the up-stream sensitising drive (block NGF / CGRP). Of the 27, 20 are expressed on the gut visceral afferent (cited relevance), ordered here by the stiffest firing gate first:

Read on the §18 afferent, the three levers do one thing. Take a sensitised afferent (visceral hypersensitivity) whose gain is raised ×1.68 above baseline; apply a lever at increasing structural strength δ (a fraction of the sensitisation removed — not a dose). For every lever the firing threshold T = spinodal − b_eff rises and the gain χ = 1/k falls monotonically back toward the baseline 1/(2g) (shown for L1; L2 and L3 are identical in direction):

This makes the inherited map a drug-class pointer for every digestive visceral-pain disorder — which lever, and which cited validated agent class realises it. It does not prescribe: it points to the mechanism class an effective agent moves.

Treatment (model reading). INHERITED analgesic target logic, applied to digestive VISCERAL PAIN. The section-18 afferent firing threshold |h_sp| (the spinodal margin) is raised -- equivalently the gain is lowered -- by ANY of three levers: L1 reduce the inward current (the alpha2delta-1 gabapentinoid class; the emerging Na_V1.8 / P2X3 nociceptor-selective classes), L2 open the K_V7 brake, L3 remove the NGF/CGRP sensitising drive. The map is a DRUG-CLASS POINTER for IBS hypersensitivity, functional abdominal pain, functional-dyspepsia pain, biliary colic, and oesophageal-spasm pain -- pointing to WHICH lever/class an effective agent moves. Class placement is [F] structural; efficacy, dose, and selectivity-in-vivo are [O]; the felt/affective pain is `mind` (the peripheral afferent term only is moved here).

A burden-weighted prioritisation of the GI nociceptor targets (inherited declared weights B=0.40 / U=0.35 / D=0.25 over cited 1–5 tiers, sorted by score; γ / |h_sp| is the structural map-place and is never folded into the clinical score) re-derives the inherited score exactly and surfaces the realised peripheral case first:

One further reading is precision (pain-selective) visceral local anaesthesia: a gut nociceptor-selective entry port (P2RX3, TRPV1, TRPA1, ASIC3) paired with a charged firing-threshold-raising blocker that can only reach its site through the open port, so the block is differential — visceral nociceptive fibres silenced while motor and light-touch are spared (mechanism shape anchored to Binshtok–Bean–Woolf, Nature 2007). The differential-block ratio, duration, and concentration are [O].

The inheritance and re-verification (drift zero), the three-lever de-sensitisation of the §18 afferent, and the burden re-derivation are forced by the substrate [V]/[F]. The firewall is non-negotiable and inherited verbatim: γ reads promoter switch-threshold STRUCTURE only — it is never a channel activation voltage, a drug potency, a dose, an in-vivo selectivity, or a clinical effect; every such magnitude, the differential-block ratio, and absolute efficacy are [O]; the lever strength δ is structural, not a dose; the L3 (NGF/CGRP) mechanism link is [O] cited biology; and the felt / affective pain is mind's (this layer moves only the peripheral afferent-gain term, the §27 firewall kept). No molecule is designed, no synthesis or dose is given, and nothing here diagnoses, treats, or prescribes — it is a proposal-only target hypothesis.