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Module 1   Lesson 19   Level 2, mechanisms

Mechanisms

Along which route can a needle do something, in which model has that been seen, and what does that route not prove?

After this lesson you can place every mechanism study on a level and in a model, and say what Liu 2021 does and does not show. No book pages: the source is the literature in the lesson.

Context expectation, ritual, relationship human Kaptchuk, Bingel Supraspinal rat, human opioids by frequency (2 Hz, 100 Hz) Han DNIC: pain inhibits pain, via the brainstem Le Bars De Qi: limbic deactivation (fMRI) Hui, Harris ascending top-down inhibition Spinal rat, mouse dorsal horn: convergent neurons inhibited Le Bars segmental reflex to the sympathetic Liu 2020 afferents Local mouse, human, post-mortem adenosine via A1, only if rotated Goldman connective tissue winds round the needle Langevin points often on fascial planes Langevin, Yandow needle Autonomic, immune mouse: Torres-Rosas, Liu low, deep, hind leg: vagus to adrenal medulla, catecholamines up, TNF and IL-6 down high, abdomen: sympathetic to spleen; sign depends on the timing
Schematic. Each box names its model; the colour says nothing about the effect size in humans.

Know by heart

  • The five levels, from bottom to top. local, spinal, supraspinal, autonomic and immune, context; mnemonic: from prick to person.
  • Local. adenosine via A1, only with rotation (Goldman 2010; mouse, A); the needle winds up connective tissue (Langevin 2001 and 2002; human and rat, B); 80 per cent of arm points on a connective tissue plane, without a baseline (Langevin and Yandow 2002; post-mortem, B).
  • Spinal and supraspinal. 2 Hz releases enkephalin, beta-endorphin and endomorphin, 100 Hz dynorphin (Han; rat, and cerebrospinal fluid in humans after TENS, B); pain elsewhere inhibits pain via the brainstem, DNIC, not point-specific (Le Bars 1979; rat, A); mnemonic: two Hz, three Es; a hundred Hz, one D.
  • The brain in humans (B). De Qi gives limbic deactivation, sharp pain gives activation (Hui 2000; fMRI, 13 healthy volunteers); verum increases μ-opioid receptor binding, sham does not (Harris 2009; PET).
  • Autonomic and immune (mouse, A). gentle and deep on the leg: PROKR2 fibres, vagus, adrenal medulla, dopamine, less TNF and IL-6 (Torres-Rosas 2014, Liu 2021); hard on the abdomen: sympathetic to the spleen, inhibitory before LPS, harmful after LPS (Liu 2020); mnemonic: gentle on the leg calms, hard on the belly rouses; rouse during the fire and you fan the flames.
  • Context. an active component in its own right: a warm relationship 62 against 44 per cent with sham (Kaptchuk 2008; RCT); expectation doubles or abolishes the effect of remifentanil (Bingel 2011).
  • The letter and the limit. A says how the evidence was obtained, not in whom: write "A (mouse)"; B is indirect or associative, C an analogy; nothing here demonstrates channels or a clinically large effect in humans.

The rest of this lesson is reference.

Mechanisms: Along which route can a needle do something, in which model has that been seen, and what does that route not prove?
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Three practice questions from this lesson

Goldman 2010. Model and route?
  1. Rat; dynorphin in the spinal cord
  2. Mouse; adenosine via A1 receptors
  3. Human; endogenous opioids via the brainstem

Answer: Mouse; adenosine via A1 receptors. Mouse, with adenosine around the point: it rose about 24-fold during the session at ST-36, and without the A1 receptor there was no pain inhibition. Opioids and dynorphin belong to other studies (Han).

In Goldman, pain inhibition did not occur in...
  1. mice given naloxone, and with a needle at a non-point
  2. mice after vagotomy, and with a needle that carried no electrical current
  3. mice without the A1 receptor, and with a needle that was not rotated

Answer: mice without the A1 receptor, and with a needle that was not rotated. Insertion alone was not enough; rotation released the purines. Vagotomy and naloxone were not tested in this study.

What did Goldman not show?
  1. That the effect only occurs on the same side
  2. That adenosine rises about 24-fold during the session
  3. That the site of the point itself matters

Answer: That the site of the point itself matters. There was no non-point for comparison. ST-36 was chosen because it is common in rodent models; a prick elsewhere in the same muscle was not tested, and adenosine after tissue stimulation is not a feature of points. The rise in adenosine and the same-side effect Goldman did show.

The rest of this lesson

In the course you get the step-by-step explanation, 16 case-based practice questions, 18 spaced-repetition flashcards, the pitfalls and the bridge to physiology with evidence grades. This lesson belongs to module 1: Foundations.

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