Emetic potential of analgesics: profiling of pungent and non-pungent vanilloids in suncus murinus (house musk shrew)

John A. Rudd, Kit M. Chu, Man P. Ngan, Man K. Wai. Chinese University of Hong Kong, Hong Kong.

Pungent vanilloids including capsaicin (CAP) and resiniferatoxin (RTX) have useful anti-nociceptive properties. Unfortunately, however, pungent compounds have a number of undesirable actions including emesis, which limits their clinical use. In the present investigations, we used S. murinus to investigate if the non/less-pungent vanilloids, olvanil (OLV) and phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV), have useful anti-nociceptive actions in the absence of a capacity to induce emesis. Female S. murinus (30-45 g) were used. Pungency was assessed using an eye-blink test. Briefly, animals were restrained and CAP (300-10000 μmol), RTX (0.03-0.01 μmol), OLV (3-100 μmol), PPAHV (0.01-0.1 μmol), or vehicle (10 μl: tween 80/ethanol/saline in a 1:1:8 ratio) was instilled into one eye and the number of blinks recorded for 5 min. Other animals were injected s.c. with CAP (10-300 μmolkg-1), RTX (0.003-0.3 μmolkg-1), OLV (1-30 μmolkg-1), PPAHV (3-100 μmolkg-1), or vehicle (2 mlkg-1) and observed for 60 min for retching and/or vomiting episodes. They were then injected i.p. with acetic acid (150 mmolkg-1, 3 mlkg-1) and writhing counted for 10 min to assess anti-nociceptive potency. Data are the mean of 4-12 determinations. Statistical significance was assessed using a one-way ANOVA with Dunnett&apos;s multiple comparisons tests. All compounds induced a significant (P<0.05) increase in blinking. Rank order of potency to cause ∼10 blinks: RTX (0.01 μmol)>PPAHV (0.1 μmol)>OLV (30 μmol)>CAP (3000 μmol). RTX, CAP and OLV but not PPAHV induced emesis: (ED5 episodes) RTX (∼0.1 μmolkg-1)>OLV (∼30 μmolkg-1)>CAP (∼300 μmolkg-1). All compounds antagonized significantly (P<0.05) acetic acid-induced writhing: (ID50) RTX (0.002 μmolkg-1)>OLV (0.8 μmolkg-1)>CAPS (7.9 μmolkg-1)>PPAHV (25.1 μmolkg-1). In conclusion, the irritant action of CAP and RTX on the eye was expected, but the activity of OLV and PPAHV suggests these compounds also have some degree of pungency in this species. The action of the compounds to antagonize acetic acid-induced writhing is consistent with pungent and non-pungent activators of TRPV1 receptors. The studies with PPAHV indicate that the useful analgesic actions of vanilloids may be dissociated from the side effect of emesis.