title: A tachykinin NK1 receptor antagonist attenuates the 4 beta-phorbol-12-myristate-13-acetate-induced nociceptive behaviour in the rat.
abstract: Antinociceptive effect of a tachykinin NK1 receptor antagonist ezlopitant [(2S,3S-cis)-2-(diphenylmethyl)-N-{(2-methoxy, 5-isopropylphenyl)methyl}-1-azabicyclo[2.2.2]octan-3-amine] was investigated in the 4beta-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 microg/kg, subcutaneous (s.c.)] blocked the PMA-induced nociceptive behaviour, suggesting that vanilloid VR1 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 NK1 receptors contribute to processing of ongoing pain associated with peripheral inflammation.
authors.affiliation: Pfizer Global Research and Development, Nagoya Laboratories, Pfizer Japan Inc., 5-2 Takeyoto, Aichi 470-2393, Japan. megumi.tsuchiya@pfizer.com
authors.forename: Megumi
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Ayano
authors.initials: A
authors.lastname: Sakakibara
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D010703:Phorbol Esters / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000502:physiology
chemical_list: D000700:Analgesics; D001596:Benzylamines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D064729:Neurokinin-1 Receptor Antagonists; D010703:Phorbol Esters; D018040:Receptors, Neurokinin-1; C008874:phorbol-12,13-diacetate; C413864:ezlopitant