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Hill Rd., She eld S10 2RX1 For many years menthol has been used in the treatment of respiratory disorders although, a bronchodilator e ect of menthol has yet to be described. Using the bronchoconstrictors capsaicin (acting via stimulating the release of neuropeptides from sensory a erents) and neurokinin A (NKA) we have raised airways resistance in the guinea-pig (GP) and studied the e ect of menthol on both capsaicin and NKA-induced bronchoconstriction in vivo. In vitro the e ect of menthol on acetylcholine (ACh) and KCl precontracted GP bronchi was also studied. 2 GP (n=13) were anaesthetized (urethane 1.5 g kg 71 , i.p.) and a bolus injection of capsaicin (7.5 mg ml 71 , i.v.) or infusion of NKA (1 mg min 71 , i.v.) was given either in the presence of air (0.81 min 71 ) or air impregnated with menthol vapour (7.5 mg l 71 ) freely breathed from a tracheal cannula via a T-piece. Airways resistance (R aw ) and ventilation were measured throughout. Bronchi of mean internal diameter (1029+73.6 mm; n=24) were removed from GP (n=16) and mounted in the Cambustion myograph. Bronchial rings were maximally precontracted with 80 mM KC1 or 2 mM ACh. Relaxation due to a cumulative dose of menthol (1 ± 3000 mM) was measured. 3 Menthol produced a signi®cant (P50.05) 51.3% reversal of the capsaicin-induced increase in R aw , and also inhibited the signi®cant (P50.05) reduction in minute ventilation (V e ) associated with the capsaicin-induced increased in R aw . Menthol also caused a signi®cant (P50.05) 41% reversal of the NKA-induced increase in R aw . The NKA-induced decrease in V e was again signi®cantly (P50.05) reversed with menthol inhalation. Menthol caused a signi®cant (P50.001) dose-dependent relaxation of KCl and ACh precontracted bronchi. 4 We have shown that menthol attenuates both capsaicin and NKA-induced bronchoconstriction in vivo and relaxes KCl and ACh preconstricted bronchi in vitro. Menthol inhibition of NKA and capsaicin-induced bronchoconstriction could be, in part, explained by a direct action of menthol on bronchial smooth muscle.

L‐Menthol inhibits both neurokinin A and capsaicin‐induced bronchoconstriction in the guinea‐pig and relaxes pre‐constricted guinea‐pig isolated bronchi. Structure‐activity relationships have been defined for the action of (−)‐menthol and related compounds on cold receptors, suggesting an action of L‐menthol at a pharmacological receptor. We have performed radioligand binding studies to characterize the binding sites for [3H]‐L‐menthol in whole cell membranes prepared from guinea‐pig lung tissue. In kinetic studies, [3H]‐L‐menthol was found to bind rapidly and reversibly. Binding of [3H]‐L‐menthol to lung membranes was found to be time‐dependant becoming fully associated to its site within 40 min, and half‐maximum association occurred within 8 min (t1/2=8 min). [3H]‐L‐menthol was fully dissociated from its binding site within 8 min, (t1/2=2 min). Inhibition studies presented a pharmacological profile of the ‘L‐menthol site’. Capsaicin, capsazepine, D‐menthol, eugenol, SCH23390 and camphor were all found to displace [3H]‐L‐menthol binding. In contrast WS3, noradrenaline, 5‐hydroxytryptamine, spiperone, flunarazine, bepridil and nicardipine were without effect. We have identified a L‐menthol binding site in the guinea‐pig, which may represent a site common to a variety of compounds. British Journal of Pharmacology (1998) 123, 481–486; doi: