TY - JOUR
T1 - Spinal infusion of opiate and alpha-2 agonists in rats
T2 - Tolerance and cross-tolerance studies
AU - Stevens, C. W.
AU - Monasky, M. S.
AU - Yaksh, T. L.
PY - 1988
Y1 - 1988
N2 - Intrathecal morphine or ST-91, an alpha-2 agonist, produce potent antinocicpetion in a number of animal models. Using osmotic minipumps and a new Y-catheter technique, we show that chronic intrathecal (i.t.) infusion of morphine (2, 6 or 20 nmol/μl/hr) or ST-91 (3, 10 or 30 nmol/μl/hr) in rats produces a dose-dependent increase in hot-plate latency 1 day after pump implant. By 4 to 5 days after initiation of chronic infusion of either drug, hot-plate latencies do not differ from saline-infused controls. Rats rendered tolerant to one of the three chronic i.t. morphine doses (2, 6 or 20 nmol/μl/hr) and tested at 7 days after initiation of infusion with a bolus i.t. dose of morphine, show a dose-dependent rightward shift in hot-plate dose-response curves. The two lower doses of chronic i.t. infusions of morphine produce parallel shifts of the subsequent i.t. administered morphine dose-response curves, but the highest chronic i.t. dose of morphine (20 nmol/μl/hr) produces a significantly greater slope of the subsequent i.t. administered morphine dose-response curve. Animals exposed to chronic i.t. infusion of one of three doses of ST-91 (3, 10 or 30 nmol/μl/hr) display a parallel, dose-dependent rightward shift to a subsequent bolus i.t. injection of ST-91. Rats rendered tolerant to chronic i.t. infusions of ST-91 showed no difference in the response to i.t. administered morphine hot-plate dose-response curves as compared to saline infused controls. Surprisingly, however, animals rendered tolerant to i.t. infusions of morphine show a parallel, dose-dependent rightward shift to i.t. administration of ST-91. Thus, an asymmetrical cross-tolerance is demonstrated whereby rats tolerant to ST-91 show no cross-tolerance to morphine, but animals tolerant to morphine show considerable cross-tolerance to ST-91. Double-reciprocal (Lineweaver-Burk) plots reveal that dose-response curves from tolerant animals exhibit a competitive antagonistic profile.
AB - Intrathecal morphine or ST-91, an alpha-2 agonist, produce potent antinocicpetion in a number of animal models. Using osmotic minipumps and a new Y-catheter technique, we show that chronic intrathecal (i.t.) infusion of morphine (2, 6 or 20 nmol/μl/hr) or ST-91 (3, 10 or 30 nmol/μl/hr) in rats produces a dose-dependent increase in hot-plate latency 1 day after pump implant. By 4 to 5 days after initiation of chronic infusion of either drug, hot-plate latencies do not differ from saline-infused controls. Rats rendered tolerant to one of the three chronic i.t. morphine doses (2, 6 or 20 nmol/μl/hr) and tested at 7 days after initiation of infusion with a bolus i.t. dose of morphine, show a dose-dependent rightward shift in hot-plate dose-response curves. The two lower doses of chronic i.t. infusions of morphine produce parallel shifts of the subsequent i.t. administered morphine dose-response curves, but the highest chronic i.t. dose of morphine (20 nmol/μl/hr) produces a significantly greater slope of the subsequent i.t. administered morphine dose-response curve. Animals exposed to chronic i.t. infusion of one of three doses of ST-91 (3, 10 or 30 nmol/μl/hr) display a parallel, dose-dependent rightward shift to a subsequent bolus i.t. injection of ST-91. Rats rendered tolerant to chronic i.t. infusions of ST-91 showed no difference in the response to i.t. administered morphine hot-plate dose-response curves as compared to saline infused controls. Surprisingly, however, animals rendered tolerant to i.t. infusions of morphine show a parallel, dose-dependent rightward shift to i.t. administration of ST-91. Thus, an asymmetrical cross-tolerance is demonstrated whereby rats tolerant to ST-91 show no cross-tolerance to morphine, but animals tolerant to morphine show considerable cross-tolerance to ST-91. Double-reciprocal (Lineweaver-Burk) plots reveal that dose-response curves from tolerant animals exhibit a competitive antagonistic profile.
UR - http://www.scopus.com/inward/record.url?scp=0023928796&partnerID=8YFLogxK
M3 - Article
C2 - 2891846
AN - SCOPUS:0023928796
SN - 0022-3565
VL - 244
SP - 63
EP - 70
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 1
ER -