Comparative effects of cyclo-oxygenase and nitric oxide synthase inhibition on the development and reversal of spinal opioid tolerance

Abstract

1. This study examined the effects of the COX inhibitors, ketorolac and ibuprofen, and the NOS inhibitor L-NAME for their potential to both inhibit the development and reverse tolerance to the antinociceptive action of morphine. 2. Repeated administration of intrathecal morphine (15 micrograms), once daily, resulted in a progressive decline of antinociceptive effect and an increase in the ED50 value in the tailflick and paw pressure tests. Co-administration of ketorolac (30 and 45 micrograms) or S(+) ibuprofen (10 micrograms) with morphine (15 micrograms) prevented the decline of antinociceptive effect and increase in ED50 value. Similar treatment with L-NAME (100 micrograms) exerted weaker effects. Administration of S(+) but not R(-) ibuprofen (10 mg kg-1) had similar effects on systemic administration of morphine (15 mg kg-1). 3. Intrathecal or systemic administration of the COX or NOS inhibitors did not alter the baseline responses in either tests. Acute keterolac or S(+) ibuprofen also did not potentiate the acute actions of spinal or systemic morphine, but chronic intrathecal administration of these agents increased the potency of acute morphine. 4. In animals already tolerant to intrathecal morphine, subsequent administration of ketorolac (30 micrograms) with morphine (15 micrograms) partially restored the antinociceptive effect and ED50 value of acute morphine, reflecting the reversal of tolerance. Intrathecal L-NAME (100 micrograms) exerted a weaker effect. 5. These data suggest that spinal COX activity, and to a lesser extent NOS activity, contributes to the development and expression of opioid tolerance. Inhibition of COX may represent a useful approach for the prevention as well as reversal of opioid tolerance.

Figure 1

Time course of the antinociceptive effect of daily administration of intrathecal morphine (15 μg) alone and in combination with ketorolac (15, 30 and 45 μg) in the (a) tailflick and (b) paw pressure tests. Morphine and the test agents were administered as a single dose. Nociceptive testing was performed 30 min following each injection. The data are presented as mean±s.e.mean for 5–7 animals. ^*Significant differences from the action of morphine (P<0.05); #Significant differences from the action of morphine/ketorolac (30 μg) (P<0.05).

Figure 2

Time course of the antinociceptive effect of daily administration of intrathecal morphine (15 μg) alone and in combination with S(+) and R(−) ibuprofen (10 μg) in the (a) tailflick and (b) paw pressure tests. Morphine and the test agents were administered as a single dose. Nociceptive testing was performed 30 min following each injection. The data are presented as mean±s.e.mean for 5–7 animals. ^*Significant differences from the action of morphine (P<0.05); #Significant differences from the action of morphine/R(−) ibuprofen alone (P<0.05).

Figure 3

Time course of the effects of S(+) and R(−) ibuprofen (10 mg kg−1) administered by intraperitoneal injection in 5% cyclodextrin on the antinociceptive response produced by daily administration of morphine (15 mg kg−1) in the (a) tailflick and (b) paw pressure tests. Nociceptive testing was performed 30 min following each injection. The data are presented as mean±s.e.mean for 5–7 animals. ^*Significant differences from the action of morphine/cyclodextrin (P<0.05); #Significant differences from the action of morphine/R(−) ibuprofen (P<0.05).

Figure 4

Time course of the antinociceptive effect of daily administration of intrathecal morphine (15 μg) alone and in combination with ketorolac (30 μg) or L-NAME (100 μg) in the (a) tailflick and (b) paw pressure tests. Morphine and the test agents were administered as a single dose. Nociceptive testing was performed 30 min following each injection. The data are presented as mean±s.e.mean for 5–7 animals. ^*Significant differences from the action of morphine (P<0.05); #Significant differences from the action of morphine/L-NAME (P<0.05).

Figure 5

Effect of ketorolac and ibuprofen isomers on the analgesic response to acute intrathecal morphine in drug naïve animals. Ketorolac and ibuprofen were co-injected with a single dose of intrathecal morphine. The response was determined 30 min after drug injection using the (a) tailflick and (b) paw pressure tests. The data are presented as mean±s.e.mean for 4–5 animals. ^*Significant differences from the action of morphine/cyclodextrin (P<0.05).

Figure 6

The effects of intrathecal ketorolac (30 μg) and L-NAME (100 μg) on established tolerance to intrathecal morphine in the paw pressure test. Tolerance was induced by administration of single morphine (15 μg) injections from days 1–5. Ketorolac or L-NAME was administered (a) with morphine or (b) without morphine from days 6–10. Morphine and the test agents were given as a single injection followed by nociceptive testing 30 min after each injection. Although not shown here, the tailflick test produced similar results. The data are presented as mean±s.e.mean for 5–7 animals. ^*Significant differences from the action of saline (P<0.05); †Significant differences from the action of morphine alone (10 days) (P<0.05); #Significantly different from the action of morphine (5 days)-morphine/L-NAME (5 days) (P<0.05).