Neurokinin -1, -2 and -3 receptors are candidates for a role in the opiate withdrawal response in guinea-pigs

2 AND -3 RECEPTORS ARE C ATE WITHDRAWAL RESPON

ES FOR A NEA-PIGS

oris A. Chahl Laboratory, Faculty ~ustralia 2308.

of Me~

tiversity of

;onists, spantide )antide and Fhe non-selective tachykinina antagonists, ar (D-Prc

~,10)SP4-11,

and aave been shown to significantly reduce the locomotor locom

d responses

:o centrally administered substance P (SP) and to nalox~

t morphine

•ithdrawal (1). The following experiments were carried ca1 out

:haracterize

:he receptors involved in opiate withdrawal by determini d

amotor and

9ehavioural responses of guinea-pigs to selective neurokinir n~

nists and by

onist and I investigating the effects of a selective NK-2 antagoJ

e morphine

:vithdrawal response. Three days before experi~ )erlment, a~

L-pigs were

SC) anaesthetized with ketamine hydrochloride (40 mg/kg mgj

(Rompun,

mg/kg SC) and ICV guide cannulae were inserted bilaterally 2 mm caudal and ar~ 2.5 rnm m m

lateral to bregma. On the day of experiment, locomotor l~ activity of guinea-pigs guinea

wecas as

measured for lh before and lh after ICV injection of the NK-1 ag onist,

Sar 9 KA4-10, 20 sarg,Met(O2)llSP, 10 nmol; the NK-2 agonist, L 3ts5,MeLeu9,Leu 10NKA4-1 or NKA, 25 nmol. SpaJ nmol nmol; the NK-3 agonist, senktide, 10 nmol; SP, 50 nmol n~ 9antide, 10 nmol, given ICV 10 min before, significantly red~ reduced the locomotor respon 9onses to 0.015), the NK-2 agonist (P=0.004) and the NK-3 atgonist the NK-1 agonist (P=0.015 Trp5,D 1 (P=0.O41) (N = 5, 5, and 6 respectively). The selective NK-2 antagonist, (Tr Trp6,8,9,Argl0)NKA4-10 •10, 50 nmol, given ICV 10 min before, did not affe( affect the he NK-2 agonist. Locomotor activity was also recorded for J lh responses to NKA or the before and 2h after injiection of morphine sulphate, 15 mg/kg SC, and for lh after injection of naloxone hlydrochloride, 15 mg/kg SC. SP1-7, 50 nmol given ICV 5min lificantly ntly increased the locomotor response to mot phine before naloxone, significantl 1: withdrawal (P=0.044) (N = 5). The NK-2 antagonist, 50 nmol ICV 10 min before naloxone significantly reduced the locomotor and digging responses to mor phine D.04) (N = 5). From these experiments it is concluded that tl all withdrawal (P=0.017; 0.04 l three NK receptors aree candidates for a role in opiate withdrawal in guinea- pigs. 1.

Johnston,

P.A. and Chahl,

Pharmacol 343: 283-288.

L.A. (1991) Naunyn-Schmiedeberg's

Arch