A tachykinin NK 1 receptor antagonist attenuates the 4β-phorbol-12-myristate-13-acetate-induced nociceptive behaviour in the rat

Abstract

Antinociceptive effect of a tachykinin NK 1 receptor antagonist ezlopitant [(2 S,3 S- cis)-2-(diphenylmethyl)- N-{(2-methoxy, 5-isopropylphenyl)methyl}-1-azabicyclo[2.2.2]octan-3-amine] was investigated in the 4β-phorbol-12-myristate-13-acetate (PMA)-induced nociceptive test in the rat. Intraplantar injection of PMA-induced paw-licking and flinching behaviour lasted up to 120 min and was accompanied by inflammatory reactions, such as swelling and invasion of granulocytes. Pretreatment with resiniferatoxin [200 μg/kg, subcutaneous (s.c.)] blocked the PMA-induced nociceptive behaviour, suggesting that vanilloid VR 1 receptor-expressing primary sensory neurons play a major role in this response. Subcutaneous pretreatment with ezlopitant (0.3–30 mg/kg) and morphine (0.3–6 mg/kg) caused a dose-dependent inhibition of the behaviour. Ezlopitant (3–30 mg/kg) given subcutaneously after PMA injection also significantly attenuated the behavioural response. When administered intrathecally, ezlopitant and a nonselective glutamate receptor antagonist MK-801 had an inhibitory effect, whereas CJ-12,191, an inactive isomer of ezlopitant, was unaffected. These results suggest that spinal tachykinin NK 1 receptors contribute to processing of ongoing pain associated with peripheral inflammation.