European Journal of Pharmacology, 192 (1991) 221-225
221
:'~' 1991 Elsevier Science Publishers B.V. (Biomedical Division)0014-2999/91/$03.50 ADONIS (X)14299991000888
FJP 51657
Antinociceptive properties of intrathecal dexmedetomidine in rats B r o c k Fisher, M a r k H. Z o r n o w , T o n y L. Y a k s h a n d B r a d l e y M. P e t e r s o n Department of Anesthestologv. Neuroanesthesia Research (M-029). Uni~:ersity of Cahfornia. San Diego. Izt Jolla. CA 92093. U.S.A. Received 6 July 1990, revised MS received 21 September 1990, accepted 16 October 1990
Dexmedetomidine is a highly selective a2-adrenoceptor agonist. In this study, the intrathecal administration of dexmedetomidine into the rat lumbar subarachnoid space produced dose-dependent, prolonged antinociception as measured by hot plate and tail flick testing. Intrathecal administration of 3 or 10 p.g of dexmedetomidine increased hot plate and tail flick latencies to cutoff values within 15 rain of injection. Animals receiving 1 p.g of intrathecal dexmedetomidine did not show any significant antinociception when compared to saline controls. The intrathecal administration of the a2-adrenoceptor antagonist, idazoxan, ablated all measurable antinociception produced by the prior injection of 10 ~g of dexmedetomidine. Dexmedetomidine; or2-Adrenoceptors; Antinociception; (intrathecal)
I. Introduction
2. Materials and methods
The intrathecal (i.t.) administration of a2-adrenoce ptor agonists produces antinociception in laboratory animals (Yaksh and Reddy, 1981; Howe et al., 1983; Eisenach et al., 1987) and analgesia in humans (Coombs et al., 1985; Coombs et al., 1986). Current evidence suggests that a2-adrenoceptors comprise a distinct population in the dorsal horn of the spinal cord and existence of these receptors has been demonstrated in a variety of species including the rat. Activation of a2adrenoceptors selectively produces analgesia which is independent of opiate receptor mechanisms (Ossipov et al., 1989). Dexmedetomidine is a highly selective and specific a2-adrenoceptor. It possesses a 7-fold greater affinity for c~2- versus al-adrenoceptors than clonidine (Virtanen et al., 1988). The purpose of this study was to determine the antinociceptive properties of dexmedetomidine when administered into the lumbar subarachnoid space of the rat. In order to verify that the observed antinociception was secondary to a2-adrenoceptor stimulation by dexmedetomidine, a selective c~2-adrenoceptor antagonist, idazoxan (Freedman and Aghajanian, 1984: Dabir~, 1986), was infused into the subarachnoid space in a subset of rats after dexmedetomidine administration.
2.2. Nociceptit,e testing
Correspondence to: M.H. Zornow. Department of Anesthesiology. Neuroanesthesia Research (M-029), University of California, San Diego, La Jolla, CA 92093, U.S.A.
Hot plate testing utilized a 52.5°C metal surface enclosed in a plexiglass box. Response latencies were measured to the nearest 0.1 s and began when the animal was placed on the surface and ended when the rat either licked a hind paw or jumped so that both hind
2. I. l.t. catheter placement and injection technique Following approval by the Institutional Animal Care Committee, 24 male Sprague-Dawley rats weighing 250300 g were anesthetized in a plexiglass chamber with 2% halothane in air. Following application of an iodine/ alcohol solution to the skin, an incision was made along the occipital ridge and the nuchal muscles were reflected. The atlanto-occipital membrane was then identified and incised through the midline. A PE 10 catheter was inserted into the subarachnoid space and advanced 8 cm caudally to the level of the lumbar enlargement. The proximal end of the catheter was externalized percutaneously, flushed with 10 p.1 of normal saline and plugged with 28 gauge wire. The incision was then sutured closed and the animals were allowed to recover in a warmed box. The animals were examined at a minimum of 48 h following catheter implantation. Any animal showing evidence of a neurological deficit was excluded from the study.
222
feet left the surface of the test chamber. In the absence of a such a response, the cutoff time was 60 s. The tail-flick response was elicited by placing the rat's tail over a slit through which a 300 W projector bulb was focused. Measurement began when the bulb was turned on and ended when the rat flicked its tail aside. Tail flick latencies were determined to the nearest 0.l s. Cutoff latency was 6 s. For each animal, baseline measurements of hot plate and tail flick latencies were obtained. The i.t. catheters were then injected with 10 yl of saline or an equal volume of saline containing 1, 3 or 10 p,g of dexmedetomidine (six animals per group) in a blinded and r a n d o m fashion. The catheter was then flushed with 10 ~,1 of saline. All animals were tested at 5, 15, 30, 60. 90, 120 and 180 rain after i.t. injection. Prior to testing, each animal was evaluated for preservation of righting and step reflexes. Testing occurred in the order of hot plate followed by tail flick. 2.3. Antagonism studies To examine the effects of the i.t. administration of an e~2-antagonist, six rats received 10 ~g of dexmedetomidine i.t. followed 15 min later by either 3, 10 or 30 p.g of idazoxan in 10 p.l of saline or saline alone. Hot plate and tail flick latencies were recorded at 5 and 15 rain after i.t. dexmedetomidine and then again at 10, 25, 40 and 70 min following the i.t. administration of idazoxan. 2.4. I.e. studies In order to further elucidate changes in rat posture and behavior after i.t. dexmedetomidine administration. internal jugular catheters were inserted into eight rats under halothane anesthesia. One end of a 6 cm segment of PE 10 tubing was placed into the internal jugular vein of each rat and the other end externalized through
MPE
(%) 120 •
the skin at the back of the neck. The catheter was flushed with heparinized saline and plugged with wire. After a 24 h recovery period, four rats were given i.v. boluses of 10/,g of dexmedetomidine and four rats w.ere given an equal volume of normal saline followed bv hot plate and tail flick testing. 2.5. Data and ,Ytati.Yti(al analvsi.Y Hot plate and tail flick results are expressed as a percentage of m a x i m u m possible effect calculated b,~ the following formula: maximum possible e f f e c t [(postdrug latency - predrug l a t e n c y ) / ( c u t o f f - predrug latency)] × 100. 1.t. d e x m e d e t o m i d m e data were analyzed using a two-way A N O V A followed by Dunnett's test for multiple comparisons versus the saline group. To test whether the administration of idazoxan reversed the observed increase in tail flick and hot plate latencies, a one factor (idazoxan dose) A N O V A was performed at each time point following the i.t. administration of idazoxan or saline. Statistical testing of the intravascular dexmedetomidine trials was by two-tailed unpaired t-tests at each of the time points following the administration of dcxmedetomidine or saline. P values < 0.05 were considcrcd to be statistically significant.
3. Results 3. l. I.t. dexmedetomidine administration I.t. administration of 3 or l0 p.g of dexmedetomidine resulted in a significant increase in hot plate latencies which were maximal within 5-15 min of injection (fig. I A). Antinociception was observed until 60 rain post-injection in 10 y g dosages and remained greater than 50% of m a x i m u m possible effect at 120 min. At 180 rain post-injection, hot plate latencies in animals that received 3 p.g of dexmedetomidine had decreased to the control value while hot plate latencies remained at 49%
HOT PLATE - DEXMEDETOMIDINE
,.. [ - -
;;:
MPE
- -
TAIL FLICK - DEXMEDETOMIDINE
(%) 1;'0
I
•
D~LT 10
&
DMt--f 3
• ~
D~E~ I S ~ IN[
80. 60. 40, 20" 01
2T.
20"
30
A
6C
90 TIME
|20 (mln)
'50
180
0
B
10
~sC
90 TIME
120
'50
180
(min)
Fig. I. H o t plate ( A ) and tail flick (B) latencies presented as a percentage o f m a x i n 3 u m possible effect ( M I ' t ( ) ill rats after the i.l. a d m i n i s t r a t i o n of d e x m e d e t o m i d i n e or saline. Values arc means + S.F. ( N - 6 per g r o u p . = P '.aluc corynanthine > yohimbine > idazoxan (Doxey et al., 1984). The authors concluded that these data indicated a greater selectivity and potency of idazoxan for o~z-adrenoceptors than either yohimbine or rauwolscine. Preliminary work indicated that an idazoxan dose-response relationship existed between 3-30 ~g when given to rats after dexmedetomidine administration, ftowever, the study results indicate that these doses were probably larger than required to antagonize dexmedetomidine produced antimxficcption. Hot plate latencies fell to baseline within 5 rain of i.t. idazoxan infusion at all doses. Measurements of tail flick latencies actually were shorter after idazoxan administration than at baseline. This study demonstrates that the lumbar subarachnoid administration of the ~2-adrenoceptor agonist, dexmedetomidine, produces dose-dependent antinociception in rats as evidenced by increases in hot plate and tail flick latencies. Further elucidation of specific adrenergic neuronal pathways involved in analgesia is required.
References
('c~mlbs, I).W., R.L Saunders, J.D. Fratkin, I_E..lensen and C.A. Murphy, 1986. ('ontinuous intrathecal hydromorphone and clonidine for intractable cancer pain, J. Neurosurg 64, 890. ('oombs, I).W., R.I,. Saunders, I). Lachance, S. Savage, T.S. Ragnarsson and L.E. Jensen, 1985, Intrathecal morphine tolerance: use of intrathecal clonidine, DADLE, and intraventricular morphine. Anesthesiology 62, 358. Dabir,L H., 1986, Idazoxan: a novel pharmacotogical too| for the study of alpha-2 adren(~ceptors, J. Pharmacol. (Paris) 17, 113.
225 Doxey, J.C., A.C. Lane, A.G. Roach and N.K. Virdee, 1984, Comparison of the alpha-2 adrenoceptor antagonist profiles of idazoxan (RX 781094), yohimbine, rauwolscine and cor3'nanthine, NaunynSchmiedeb. Arch. Pharmacol. 325, 136. Doxey, J.C., A.G. Roach and C.F.C. Smith, 1983, Studies on RX 781094: a selective, potent and specific antagonist of alpha-2 adrenoceptors, Br. J. Pharmacol. 78, 489. Doze, V.A., B.-X. Chen and M. Maze, 1989, Dexmedetomidine produces a hypnotic-anesthetic action in rats via activation of central alpha-2 adrenoceptors, Anesthesiology 71, 75. Eisenach, J.C., D.M. Dewan, J.C. Rose and J.M. Angelo, 1987. Epidural clonidine produces antinociception, but not hypotension, in sheep, Anesthesiology 66, 496. Freedman, J.E. and G.K. Aghajanian, 1984, ldazoxan (RX 781094) selectively antagonizes a,-adrenoceptors on rat central neurons. European J. Pharmacol. 105, 265. Howc, J.R., J.Y. Wang and T.L. Yaksh, 1983, Selective antagonism of the antinociceptive effect of intrathecally applied alpha-adrenergic agonists by intrathecal prazosin and intrathecal yohimbine, J. Pharmacol. Exp. Ther. 224, 552. Kawasaki, K., H. Takesue and A. Matsuhita, 1978, MCxlulation of spinal reflex activities in acute aspinal rats and alpha-adrenergic agonist clonidine, Jap. J. Pharmacol. 28, 165. Ossipov. M.H., L.J. Suarez and T.C. Spaulding, 1989. Antintx:iceptive interactions between alpha-2 adrenergic and opiate agonists at the spinal level in rodents, Anesth. Analg. 68, 194. Reddy, S.R., J.l,. Maderdrut and T.I,. Yaksh, 1980, Spinal cord
pharmacology of adrenergic agonist-mediated antinociception, J. Pharmacol. Exp. Ther. 213, 525. Reddy, S.R. and T.I,. Yaksh, 1980. Spinal noradrenergic terminal system mediates antinociception, Brain Res. 189, 391. Scheinin, M., A. Kallio, M. Koulu, J. Viikari and H. Scheinin, 1987, Sedative and cardiovascular effects of medetomidine, a novel selective alpha-2 adrenoceptor agonist, in healthy volunteers, Br. J. Clin. Pharmacol. 24, 443. Spaulding, T.C., J.J, Venafro, M.G. Ma and S. Fielding, 1979, The dissociation of antin~x:iceptive effect of clonidine from supraspinal structures, Neuropharmacology 18, 103. Sullivan, A.F., M.R. Dashwt~od and A.H. l)ickenson, 1987, az-Adrenoceptor modulation of nociception in rat spinal cord: location, effects and interactions with morphine. European J. Pharmacol. 138, 169. Virtanen, R.. J.-M. Savola, V. Saano and L. Nyman. 1988, Characterization of the selectivity, specificity and potency of medetomidine as an o~z-adrenoceptor agonist, European J. Pharmacol. 150, 9. Yaksh, T.L., 1985, Pharmacology of spinal adrenergic systems which mcx,tulate spinal nociceptive processing. Pharmacol. Biochem. Behay. 22, 845. Yaksh, T.I,. and S.V.R. Reddy, 1981. Studies in the primate on the analgetic effects ass~xziated with intrathecal actions of opiates, ct-adrenergic agonists, and baclofen, Anesthesiology 54. 451. Zemlan, F.P., S.A. Corrigan and I).W. Pfaff, 198(I, Noradrenergic and serotonergic mediation of spinal analgesia mechanisms, European J. Pharmacol. 61, 111.
221
:'~' 1991 Elsevier Science Publishers B.V. (Biomedical Division)0014-2999/91/$03.50 ADONIS (X)14299991000888
FJP 51657
Antinociceptive properties of intrathecal dexmedetomidine in rats B r o c k Fisher, M a r k H. Z o r n o w , T o n y L. Y a k s h a n d B r a d l e y M. P e t e r s o n Department of Anesthestologv. Neuroanesthesia Research (M-029). Uni~:ersity of Cahfornia. San Diego. Izt Jolla. CA 92093. U.S.A. Received 6 July 1990, revised MS received 21 September 1990, accepted 16 October 1990
Dexmedetomidine is a highly selective a2-adrenoceptor agonist. In this study, the intrathecal administration of dexmedetomidine into the rat lumbar subarachnoid space produced dose-dependent, prolonged antinociception as measured by hot plate and tail flick testing. Intrathecal administration of 3 or 10 p.g of dexmedetomidine increased hot plate and tail flick latencies to cutoff values within 15 rain of injection. Animals receiving 1 p.g of intrathecal dexmedetomidine did not show any significant antinociception when compared to saline controls. The intrathecal administration of the a2-adrenoceptor antagonist, idazoxan, ablated all measurable antinociception produced by the prior injection of 10 ~g of dexmedetomidine. Dexmedetomidine; or2-Adrenoceptors; Antinociception; (intrathecal)
I. Introduction
2. Materials and methods
The intrathecal (i.t.) administration of a2-adrenoce ptor agonists produces antinociception in laboratory animals (Yaksh and Reddy, 1981; Howe et al., 1983; Eisenach et al., 1987) and analgesia in humans (Coombs et al., 1985; Coombs et al., 1986). Current evidence suggests that a2-adrenoceptors comprise a distinct population in the dorsal horn of the spinal cord and existence of these receptors has been demonstrated in a variety of species including the rat. Activation of a2adrenoceptors selectively produces analgesia which is independent of opiate receptor mechanisms (Ossipov et al., 1989). Dexmedetomidine is a highly selective and specific a2-adrenoceptor. It possesses a 7-fold greater affinity for c~2- versus al-adrenoceptors than clonidine (Virtanen et al., 1988). The purpose of this study was to determine the antinociceptive properties of dexmedetomidine when administered into the lumbar subarachnoid space of the rat. In order to verify that the observed antinociception was secondary to a2-adrenoceptor stimulation by dexmedetomidine, a selective c~2-adrenoceptor antagonist, idazoxan (Freedman and Aghajanian, 1984: Dabir~, 1986), was infused into the subarachnoid space in a subset of rats after dexmedetomidine administration.
2.2. Nociceptit,e testing
Correspondence to: M.H. Zornow. Department of Anesthesiology. Neuroanesthesia Research (M-029), University of California, San Diego, La Jolla, CA 92093, U.S.A.
Hot plate testing utilized a 52.5°C metal surface enclosed in a plexiglass box. Response latencies were measured to the nearest 0.1 s and began when the animal was placed on the surface and ended when the rat either licked a hind paw or jumped so that both hind
2. I. l.t. catheter placement and injection technique Following approval by the Institutional Animal Care Committee, 24 male Sprague-Dawley rats weighing 250300 g were anesthetized in a plexiglass chamber with 2% halothane in air. Following application of an iodine/ alcohol solution to the skin, an incision was made along the occipital ridge and the nuchal muscles were reflected. The atlanto-occipital membrane was then identified and incised through the midline. A PE 10 catheter was inserted into the subarachnoid space and advanced 8 cm caudally to the level of the lumbar enlargement. The proximal end of the catheter was externalized percutaneously, flushed with 10 p.1 of normal saline and plugged with 28 gauge wire. The incision was then sutured closed and the animals were allowed to recover in a warmed box. The animals were examined at a minimum of 48 h following catheter implantation. Any animal showing evidence of a neurological deficit was excluded from the study.
222
feet left the surface of the test chamber. In the absence of a such a response, the cutoff time was 60 s. The tail-flick response was elicited by placing the rat's tail over a slit through which a 300 W projector bulb was focused. Measurement began when the bulb was turned on and ended when the rat flicked its tail aside. Tail flick latencies were determined to the nearest 0.l s. Cutoff latency was 6 s. For each animal, baseline measurements of hot plate and tail flick latencies were obtained. The i.t. catheters were then injected with 10 yl of saline or an equal volume of saline containing 1, 3 or 10 p,g of dexmedetomidine (six animals per group) in a blinded and r a n d o m fashion. The catheter was then flushed with 10 ~,1 of saline. All animals were tested at 5, 15, 30, 60. 90, 120 and 180 rain after i.t. injection. Prior to testing, each animal was evaluated for preservation of righting and step reflexes. Testing occurred in the order of hot plate followed by tail flick. 2.3. Antagonism studies To examine the effects of the i.t. administration of an e~2-antagonist, six rats received 10 ~g of dexmedetomidine i.t. followed 15 min later by either 3, 10 or 30 p.g of idazoxan in 10 p.l of saline or saline alone. Hot plate and tail flick latencies were recorded at 5 and 15 rain after i.t. dexmedetomidine and then again at 10, 25, 40 and 70 min following the i.t. administration of idazoxan. 2.4. I.e. studies In order to further elucidate changes in rat posture and behavior after i.t. dexmedetomidine administration. internal jugular catheters were inserted into eight rats under halothane anesthesia. One end of a 6 cm segment of PE 10 tubing was placed into the internal jugular vein of each rat and the other end externalized through
MPE
(%) 120 •
the skin at the back of the neck. The catheter was flushed with heparinized saline and plugged with wire. After a 24 h recovery period, four rats were given i.v. boluses of 10/,g of dexmedetomidine and four rats w.ere given an equal volume of normal saline followed bv hot plate and tail flick testing. 2.5. Data and ,Ytati.Yti(al analvsi.Y Hot plate and tail flick results are expressed as a percentage of m a x i m u m possible effect calculated b,~ the following formula: maximum possible e f f e c t [(postdrug latency - predrug l a t e n c y ) / ( c u t o f f - predrug latency)] × 100. 1.t. d e x m e d e t o m i d m e data were analyzed using a two-way A N O V A followed by Dunnett's test for multiple comparisons versus the saline group. To test whether the administration of idazoxan reversed the observed increase in tail flick and hot plate latencies, a one factor (idazoxan dose) A N O V A was performed at each time point following the i.t. administration of idazoxan or saline. Statistical testing of the intravascular dexmedetomidine trials was by two-tailed unpaired t-tests at each of the time points following the administration of dcxmedetomidine or saline. P values < 0.05 were considcrcd to be statistically significant.
3. Results 3. l. I.t. dexmedetomidine administration I.t. administration of 3 or l0 p.g of dexmedetomidine resulted in a significant increase in hot plate latencies which were maximal within 5-15 min of injection (fig. I A). Antinociception was observed until 60 rain post-injection in 10 y g dosages and remained greater than 50% of m a x i m u m possible effect at 120 min. At 180 rain post-injection, hot plate latencies in animals that received 3 p.g of dexmedetomidine had decreased to the control value while hot plate latencies remained at 49%
HOT PLATE - DEXMEDETOMIDINE
,.. [ - -
;;:
MPE
- -
TAIL FLICK - DEXMEDETOMIDINE
(%) 1;'0
I
•
D~LT 10
&
DMt--f 3
• ~
D~E~ I S ~ IN[
80. 60. 40, 20" 01
2T.
20"
30
A
6C
90 TIME
|20 (mln)
'50
180
0
B
10
~sC
90 TIME
120
'50
180
(min)
Fig. I. H o t plate ( A ) and tail flick (B) latencies presented as a percentage o f m a x i n 3 u m possible effect ( M I ' t ( ) ill rats after the i.l. a d m i n i s t r a t i o n of d e x m e d e t o m i d i n e or saline. Values arc means + S.F. ( N - 6 per g r o u p . = P '.aluc corynanthine > yohimbine > idazoxan (Doxey et al., 1984). The authors concluded that these data indicated a greater selectivity and potency of idazoxan for o~z-adrenoceptors than either yohimbine or rauwolscine. Preliminary work indicated that an idazoxan dose-response relationship existed between 3-30 ~g when given to rats after dexmedetomidine administration, ftowever, the study results indicate that these doses were probably larger than required to antagonize dexmedetomidine produced antimxficcption. Hot plate latencies fell to baseline within 5 rain of i.t. idazoxan infusion at all doses. Measurements of tail flick latencies actually were shorter after idazoxan administration than at baseline. This study demonstrates that the lumbar subarachnoid administration of the ~2-adrenoceptor agonist, dexmedetomidine, produces dose-dependent antinociception in rats as evidenced by increases in hot plate and tail flick latencies. Further elucidation of specific adrenergic neuronal pathways involved in analgesia is required.
References
('c~mlbs, I).W., R.L Saunders, J.D. Fratkin, I_E..lensen and C.A. Murphy, 1986. ('ontinuous intrathecal hydromorphone and clonidine for intractable cancer pain, J. Neurosurg 64, 890. ('oombs, I).W., R.I,. Saunders, I). Lachance, S. Savage, T.S. Ragnarsson and L.E. Jensen, 1985, Intrathecal morphine tolerance: use of intrathecal clonidine, DADLE, and intraventricular morphine. Anesthesiology 62, 358. Dabir,L H., 1986, Idazoxan: a novel pharmacotogical too| for the study of alpha-2 adren(~ceptors, J. Pharmacol. (Paris) 17, 113.
225 Doxey, J.C., A.C. Lane, A.G. Roach and N.K. Virdee, 1984, Comparison of the alpha-2 adrenoceptor antagonist profiles of idazoxan (RX 781094), yohimbine, rauwolscine and cor3'nanthine, NaunynSchmiedeb. Arch. Pharmacol. 325, 136. Doxey, J.C., A.G. Roach and C.F.C. Smith, 1983, Studies on RX 781094: a selective, potent and specific antagonist of alpha-2 adrenoceptors, Br. J. Pharmacol. 78, 489. Doze, V.A., B.-X. Chen and M. Maze, 1989, Dexmedetomidine produces a hypnotic-anesthetic action in rats via activation of central alpha-2 adrenoceptors, Anesthesiology 71, 75. Eisenach, J.C., D.M. Dewan, J.C. Rose and J.M. Angelo, 1987. Epidural clonidine produces antinociception, but not hypotension, in sheep, Anesthesiology 66, 496. Freedman, J.E. and G.K. Aghajanian, 1984, ldazoxan (RX 781094) selectively antagonizes a,-adrenoceptors on rat central neurons. European J. Pharmacol. 105, 265. Howc, J.R., J.Y. Wang and T.L. Yaksh, 1983, Selective antagonism of the antinociceptive effect of intrathecally applied alpha-adrenergic agonists by intrathecal prazosin and intrathecal yohimbine, J. Pharmacol. Exp. Ther. 224, 552. Kawasaki, K., H. Takesue and A. Matsuhita, 1978, MCxlulation of spinal reflex activities in acute aspinal rats and alpha-adrenergic agonist clonidine, Jap. J. Pharmacol. 28, 165. Ossipov. M.H., L.J. Suarez and T.C. Spaulding, 1989. Antintx:iceptive interactions between alpha-2 adrenergic and opiate agonists at the spinal level in rodents, Anesth. Analg. 68, 194. Reddy, S.R., J.l,. Maderdrut and T.I,. Yaksh, 1980, Spinal cord
pharmacology of adrenergic agonist-mediated antinociception, J. Pharmacol. Exp. Ther. 213, 525. Reddy, S.R. and T.I,. Yaksh, 1980. Spinal noradrenergic terminal system mediates antinociception, Brain Res. 189, 391. Scheinin, M., A. Kallio, M. Koulu, J. Viikari and H. Scheinin, 1987, Sedative and cardiovascular effects of medetomidine, a novel selective alpha-2 adrenoceptor agonist, in healthy volunteers, Br. J. Clin. Pharmacol. 24, 443. Spaulding, T.C., J.J, Venafro, M.G. Ma and S. Fielding, 1979, The dissociation of antin~x:iceptive effect of clonidine from supraspinal structures, Neuropharmacology 18, 103. Sullivan, A.F., M.R. Dashwt~od and A.H. l)ickenson, 1987, az-Adrenoceptor modulation of nociception in rat spinal cord: location, effects and interactions with morphine. European J. Pharmacol. 138, 169. Virtanen, R.. J.-M. Savola, V. Saano and L. Nyman. 1988, Characterization of the selectivity, specificity and potency of medetomidine as an o~z-adrenoceptor agonist, European J. Pharmacol. 150, 9. Yaksh, T.L., 1985, Pharmacology of spinal adrenergic systems which mcx,tulate spinal nociceptive processing. Pharmacol. Biochem. Behay. 22, 845. Yaksh, T.I,. and S.V.R. Reddy, 1981. Studies in the primate on the analgetic effects ass~xziated with intrathecal actions of opiates, ct-adrenergic agonists, and baclofen, Anesthesiology 54. 451. Zemlan, F.P., S.A. Corrigan and I).W. Pfaff, 198(I, Noradrenergic and serotonergic mediation of spinal analgesia mechanisms, European J. Pharmacol. 61, 111.
