Intradermal injection of histamine into forearm skin produces the classic Lewis triple response. The red spot and wheal are direct effects on the microvasculature, while the surrounding spreading flare is produced by:

• A Systemic absorption of histamine causing generalised vasodilatation
• B An axon reflex in sensory C fibres releasing substance P and CGRP from adjacent nerve terminals ✓
• C Local release of norepinephrine from sympathetic vasomotor nerves
• D Complement activation generating C3a and C5a in the dermis

Explanation

The triple response consists of a red spot from local capillary dilatation, a wheal from increased permeability of postcapillary venules, and a bright red irregular flare extending several centimetres beyond the injection site. The flare is mediated by an axon reflex: histamine stimulates nociceptive C-fibre endings, impulses travel antidromically along collateral branches, and vasodilator neuropeptides such as substance P and CGRP are released peripherally. This reflex explains flare spread well beyond the area reached by diffusing histamine.

Reference: Ganong's Review of Medical Physiology, 26th ed.

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