Involvement of spinal tyrosine kinase in inflammatory and N-methyl-D-aspartate-induced hyperalgesia in rats.
Phosphorylation of a subunit of N-methyl-D-aspartate (NMDA) receptor by protein tyrosine kinase (PTK) Src or Trk is known to enhance its channel activity. We examined whether a spinally administered selective PTK inhibitor, lavendustin A, which has high affinity for Src and Trk tyrosine kinases, could influence the development and maintenance of inflammatory hyperalgesia or NMDA-induced hyperalgesia. Inflammation was induced by injection of a mixture of carrageenan and kaolin into the tail base of rats. In another group of rats, hyperalgesia was induced by intrathecal administration of NMDA. Intrathecal administration of lavendustin A (1.0 microg) or NMDA receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptane-5,10-iminemaleate, MK-801 (3.0 microg) before injection of a mixture of carrageenan and kaolin or after the development of inflammation inhibited carrageenan-kaolin-induced mechanical hyperalgesia. Intrathecal injection of 1.0 microg NMDA produced thermal and mechanical hyperalgesia. Co-administration of 1.0 microg lavendustin A with NMDA significantly reduced the duration of spontaneous pain behaviour and inhibited NMDA-induced hyperalgesia. Lavendustin A itself did not cause any sedation, motor impairment or analgesia. Our results suggest that inhibition of PTK could be therapeutically effective as an analgesic in some NMDA receptor-mediated hyperalgesic states.
Sato
Eiru
E
Department of Anesthesiology, Koshigaya Hospital, Dokkyo University, School of Medicine, 2-1-50 Minami-Koshigaya, Saitama 343-8555, Koshigaya City, Japan. e-sato@wc4.so-net.ne.jp
Takano
Yoshito
Y
Kuno
Yuichiro
Y
Takano
Manami
M
Sato
Isao
I
D000818:Animals; D002351:Carrageenan / Q000008:administration & dosage / Q000009:adverse effects; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced* / Q000150:complications / Q000517:prevention & control; D007249:Inflammation / Q000139:chemically induced* / Q000150:complications / Q000517:prevention & control; D007278:Injections, Spinal; D007616:Kaolin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D016202:N-Methylaspartate / Q000008:administration & dosage* / Q000009:adverse effects*; D010146:Pain; D010147:Pain Measurement; D010636:Phenols / Q000008:administration & dosage / Q000493:pharmacokinetics; D011505:Protein-Tyrosine Kinases / Q000008:administration & dosage* / Q000009:adverse effects* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology*
D010636:Phenols; D016194:Receptors, N-Methyl-D-Aspartate; D007616:Kaolin; C062898:lavendustin A; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D002351:Carrageenan; D011505:Protein-Tyrosine Kinases