CUTANEOUS RESPONSE TO ANTICHOLINERGICS - EVIDENCE FOR MUSCARINIC RECEPTOR SUBTYPE PARTICIPATION

We conducted a series of experiments to determine if anticholinergics induce immediate cutaneous wheal-and-flare responses in normal volunteers. We performed intradermal skin testing in seven healthy volunteers (three atopic and four nonatopic) with 20 nmol of atropine. All subjects had an immediate wheal-and-flare response to atropine. To determine if this cutaneous response was due to anticholinergics in general, skin testing was also performed to scopolamine and ipratropium. These agents also produced immediate wheal-and-flare responses in all subjects, but they less potent than atropine. Pretreatment with antihistamines equivalently inhibited wheal-and-flare responses to both histamine and atropine, indicating a possible mast cell role. The potential role of M1, M2, and M3 muscarinic receptor subtypes was evaluated by use of the selective antagonists, pirenzepine (M1), 11[[2-1[(diethylamino)methyl]-1-piperidinyl]-acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (AFDX-116) (M2), and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) (M3). Cutaneous wheal responses induced by pirenzepine and 4-DAMP were relatively equivalent and larger than responses induced by AFDX-116 at doses < 200 nmol. At 200 nmol, all three muscarinic receptor subtype antagonists induced equivalent wheal formation. We then compared the cutaneous wheal responses to these specific muscarinic receptor antagonists based on their relative affinity for their respective muscarinic receptor subtype. This comparison suggested that M1 or M2, but not M3, muscarinic receptor subtypes may be important in anticholinergic-induced cutaneous wheal-and-flare responses. We propose that there may be an M1 or M2 muscarinic autoreceptor that inhibits the release of acetylcholine and other neurotransmitters. Anticholinergic-induced cutaneous wheal-and-flare responses may then result from inhibition of this autoreceptor, thereby allowing release of acetylcholine and other neurotransmitters leading to an immediate wheal-and-flare response.