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Time-course of physical abstinence and tolerance recovery after spinal continuous infusion of μ agonists in the rat
S127 Poster 205 A PREUMINABY EVALUATION OF ANALGESIC LATENCY OF BLACK Mon-Tues EPIDUBAL ANALGESICS IN RABBITS. AUTHORS: &c Warn. MD.** JM HBerdPhD,b* EJ Simon,PhD,C*C Rosenberg, PhD,d*D Up* Exhibit Hall H Turndorf,MD ??* Span. A BatistaMD. Abs No 248 AFFIUATIGN: Departments Anesthesidogy a, Psychiatry,b Pharmacology,c Environmental Medicine,d*Neuro-surg.* N.Y.U School of Med. N.Y, N.Y., 10016, USA. I AIM OF INVESTIGATION: The analgesiclatencyof epkfural(Ed) normalsaline(S), morphine (M), m&ertdine (D), fentanyl (F), donMine (C), C+M, S+C, and base line contrd (B) were compared for 4 hours, in unanesthetizedrabbits. METHODS: One week afteraseptic implantationof lumbarEpi catheters,49 AlbinoNew Zealand rabbitsweighing34 kg were studiedin 6 groups(G)Analge Latency(L):The interval between time zero to hindlimbwithdrawalwas tested, after electric stimulation’ via skin etectrodeson the lower back, using 1 hers, 3 m set and 50 vdts from a S6 Grass Stimulator.L was determinedbeforeand after each injectionand repeatedhourlyfor 4 hoursI. Gl (n=6) Control:L testingonly,withoutinjection or surgery.02 (n=S) S 0.2 ml Ed. G3 (n=S) M 0.4 mg In 0.4 rd. G4 (n=7) D 0.75 mg/kg in 0.2 rd. 65 (n=6) F 7 ug in 0.2 ml. G6 (n=6) C 0.03 mg in 0.2 ml. G7 (n=S) M 0,2 mg + C 0.03 mg. G6 (n=6) S 0.2 ml. and followed 2 hourstater by C 0.03 mg. Stattatical ?? rlysir: The maximum, mean, and final values of L were compared among the 8 groups using analysisof covartanceadjustingfor the pretreatmentvalues.Tukey’stest was used for pair-wisemultiplecomparisonsat p< 0.05. RESULTS: Within4 hours,D prolongedL more than others in this study.(Fig.l) Tukey’stest revealedstatisticalsignificance in nearlyall pairs invdving D viz. G4:G8, G4:G7, G4:G5, G4:G3, G4:G2, G4:Gl. CONCLUSION: Within4 hours,Ed D prdonged L morethan othersin this study.This - mparisionofAn&#sicLatencyofB& is consistentwith the findings of a sh&k tit&ion threshold st”d~ in primate ‘. The liMcIMulll mh u r C-u.-’ v QI u . I c, c, M,C & s+c octand water coefficientfor D is 36.6 as compared with 1.42 for M . After Epi injection, r. _____ ml- -___ _._,_,>_. 4.5 __A ____ L^^ ?? rr*lr.. 1 *I-,._,.,._‘%r ,k.3” 4” _...^I_ ^ A..^^.. .n.w I *r.ec. u erxerswr more qunxry 6, and is more rapklly taken up by the spinal cord ‘.
TITLE:
of
1. Eisenach JC et
cd.Anesth@~@y~ 6&4S&50%&9”. 2,YakshTLetaLAnesMesbkgy : , . 3. Gouriay GK et al. Pain 31:297-3C6,1937. 4. Glynn CJ el al. Anestheskkgy 55: 520-526,1931. necdheskbgy 67: an-388,1987. 5.SiWrUnSetd.A ;: Cou~zolJ~~w 67: S75-376,1337. llmthdology 63:483-46% 1935.
TIME-COURSE OF PHYSICAL ABSTINENCE AND TOLERANCE RECOVERY AFTER SPINAL CONTINUOUS INFUSION OF CI_ AGONISTS IN THE RAT. M Sosnowskil and TL Yaksha. Departments of Anesthesiology. lInstitut Bordet, Universite Libre de Bruxelles. Brussels, Belgium.2University of California San Diego, La Jolla, California.
Poster 206 BLACK Mon-Tues Exhibit Hall Abs No
249
AIM OF INVESTIGATION; To examine the characteristics of spinal withdrawal and tolerance,to opioids the time course of these two receptor mediated effect were studied after completion of 7 days chronic exposure of the spinal cord to sufentanil (S) or morphine (Ml two p agents differing in eflkacy. METHODS: Male Sprague-Dawley rats were implanted with spinal catheters connected to osmotic minipumps filled with equiactive concentration of drug solutions (S:O.6nmol/h; M:20nmol/h) or saline. They were then examined for spontaneous withdrawal behavior. For tolerance recovery, hot plate (HP) dose-response curves (DRC) of S. M. and saline infused animals are constructed for morphine at 3 hours, 9 and 18 days following cessation of the infusion: at 3 hours post infusion S and saline groups were probed for sufentantl. Each animal was used for a single experiment. RESULTS; Abstinence signs started after 3 hours and were maximum at 9 hours and 1 day post withdrawal for both agonists. There was no difference in the time course or magnitude of withdrawal following S or M infusion. Some classical naloxone precipitated withdrawal signs (pnnping. diarrhea) were not present. Spinally mediated withdrawal signs were evidenced (hind limb hyperextention following light brush across the flanks). Examining the M and S-HP activity at day 1 after termination of infusion in M and S infused animals showed a 44 and 3-fold shift on the M and S-DRC respectively. Examining M-DRC revealed a statistical1 y significant recovery by 9daysinMandSinfksedanimals. CONCLUSIONS: It is believed that tolerance is a function of down-regulation - uncoupling of the receptor: the different magnitude of tolerance for M and S is predicted by receptor theory in the basis of different efficacy. The different time-course of withdrawal vs recovery of sensitivity to the opioid receptor however argues for distinguishable mechanisms.
TITLE:
of
1. Eisenach JC et
cd.Anesth@~@y~ 6&4S&50%&9”. 2,YakshTLetaLAnesMesbkgy : , . 3. Gouriay GK et al. Pain 31:297-3C6,1937. 4. Glynn CJ el al. Anestheskkgy 55: 520-526,1931. necdheskbgy 67: an-388,1987. 5.SiWrUnSetd.A ;: Cou~zolJ~~w 67: S75-376,1337. llmthdology 63:483-46% 1935.
TIME-COURSE OF PHYSICAL ABSTINENCE AND TOLERANCE RECOVERY AFTER SPINAL CONTINUOUS INFUSION OF CI_ AGONISTS IN THE RAT. M Sosnowskil and TL Yaksha. Departments of Anesthesiology. lInstitut Bordet, Universite Libre de Bruxelles. Brussels, Belgium.2University of California San Diego, La Jolla, California.
Poster 206 BLACK Mon-Tues Exhibit Hall Abs No
249
AIM OF INVESTIGATION; To examine the characteristics of spinal withdrawal and tolerance,to opioids the time course of these two receptor mediated effect were studied after completion of 7 days chronic exposure of the spinal cord to sufentanil (S) or morphine (Ml two p agents differing in eflkacy. METHODS: Male Sprague-Dawley rats were implanted with spinal catheters connected to osmotic minipumps filled with equiactive concentration of drug solutions (S:O.6nmol/h; M:20nmol/h) or saline. They were then examined for spontaneous withdrawal behavior. For tolerance recovery, hot plate (HP) dose-response curves (DRC) of S. M. and saline infused animals are constructed for morphine at 3 hours, 9 and 18 days following cessation of the infusion: at 3 hours post infusion S and saline groups were probed for sufentantl. Each animal was used for a single experiment. RESULTS; Abstinence signs started after 3 hours and were maximum at 9 hours and 1 day post withdrawal for both agonists. There was no difference in the time course or magnitude of withdrawal following S or M infusion. Some classical naloxone precipitated withdrawal signs (pnnping. diarrhea) were not present. Spinally mediated withdrawal signs were evidenced (hind limb hyperextention following light brush across the flanks). Examining the M and S-HP activity at day 1 after termination of infusion in M and S infused animals showed a 44 and 3-fold shift on the M and S-DRC respectively. Examining M-DRC revealed a statistical1 y significant recovery by 9daysinMandSinfksedanimals. CONCLUSIONS: It is believed that tolerance is a function of down-regulation - uncoupling of the receptor: the different magnitude of tolerance for M and S is predicted by receptor theory in the basis of different efficacy. The different time-course of withdrawal vs recovery of sensitivity to the opioid receptor however argues for distinguishable mechanisms.