Augmentation of spinal morphine analgesia and inhibition of tolerance by low doses of mu- and delta-opioid receptor antagonists

Abstract

Background and purpose: Ultralow doses of naltrexone, a non-selective opioid antagonist, have previously been found to augment acute morphine analgesia and block the development of tolerance to this effect. Since morphine tolerance is dependent on the activity of micro and delta receptors, the present study investigated the effects of ultralow doses of antagonists selective for these receptor types on morphine analgesia and tolerance in tests of thermal and mechanical nociception.

Experimental approach: Effects of intrathecal administration of mu-receptor antagonists, CTOP (0.01 ng) or CTAP (0.001 ng), or a delta-receptor antagonist, naltrindole (0.01 ng), on spinal morphine analgesia and tolerance were evaluated using the tail-flick and paw-pressure tests in rats.

Key results: Both micro and delta antagonists augmented analgesia produced by a sub-maximal (5 microg) or maximal (15 microg) dose of morphine. Administration of the antagonists with morphine (15 microg) for 5 days inhibited the progressive decline of analgesia and prevented the loss of morphine potency. In animals exhibiting tolerance to morphine, administration of the antagonists with morphine produced a recovery of the analgesic response and restored morphine potency.

Conclusions and implications: Combining ultralow doses of micro- or delta-receptor antagonists with spinal morphine augmented the acute analgesic effects, inhibited the induction of chronic tolerance and reversed established tolerance. The remarkably similar effects of micro- and delta-opioid receptor antagonists on morphine analgesia and tolerance are interpreted in terms of blockade of the latent excitatory effects of the agonist that limit expression of its full activity.

Figure 1

Time course of the effects of ultralow doses of intrathecal CTOP (0.01 ng) and naltrindole (NTI; 0.01 ng) on the acute antinociceptive action of a submaximal dose of morphine (Mor; 5 μg) in the (a) tail-flick and (b) paw-pressure test. Morphine was administered with CTOP or NTI as a single intrathecal injection. Nociceptive testing was performed every 10 min post-injection for the first hour and every 30 min for the following 2 h. The data are expressed as mean±s.e.m. for five to six animals. Significant differences from the action of morphine alone: ^*P<0.01, ^**P<0.001. CTOP, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂; NTI, naltrindole.

Figure 2

Time course of the effects of ultralow doses of intrathecal CTOP (0.01 ng), CTAP (0.001 ng) and naltrindole (NTI; 0.01 ng) on the acute antinociceptive action of a maximal dose of morphine (Mor; 15 μg) in the (a) tail-flick and (b) paw-pressure test. Morphine was administered with CTOP, CTAP, or NTI as a single intrathecal injection. Nociceptive testing was performed every 10 min post-injection for the first hour and every 30 min for the following 2 h. The data are expressed as mean±s.e.m. for four to six animals. Significant differences from the action of morphine alone: ^*P<0.01, ^**P<0.001. CTAP, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂; CTOP, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂; NTI, naltrindole.

Figure 3

Effects of ultralow doses of opioid receptor antagonists on the induction of morphine tolerance in the tail-flick test. (a) Time course of the effects of intrathecal CTOP (0.01 ng), CTAP (0.001 ng), and naltrindole (NTI; 0.01 ng) on the induction of tolerance to chronic morphine (Mor; 15 μg) in the tail-flick test. Morphine and CTOP, CTAP, or NTI were administered as a single intrathecal injection once daily for 5 days. Nociceptive testing was performed 60 min after each injection. The data are expressed as mean±s.e.m. for four to seven animals. (b) Cumulative dose–response curves for the antinociceptive effects of acute morphine in the treatment groups represented in (a). The dose–response curves were obtained 24 h after termination of the chronic drug treatment. Ascending doses of intrathecal morphine were given every 30 min and the antinocieptive response was measured in the tail-flick test 25 min after each injection. Significant differences from the action of morphine alone: ^*P<0.05, ^**P<0.01. CTAP, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂; CTOP, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂; NTI, naltrindole.

Figure 4

Effects of ultralow doses of opioid receptor antagonists on the induction of morphine tolerance in the paw-pressure test. (a) Time course of the effects of intrathecal CTOP (0.01 ng), CTAP (0.001 ng) and naltrindole (NTI; 0.01 ng) on the induction of tolerance to chronic morphine (Mor; 15 μg) in the paw-pressure test. Morphine and CTOP, CTAP, or NTI were administered as a single intrathecal injection once daily for 5 days. Nociceptive testing was performed 60 min after each injection. The data are expressed as mean±s.e.m. for four to seven animals. (b) Cumulative dose–response curves for the antinociceptive effects of acute morphine in the treatment groups represented in (a). The dose–response curves were obtained 24 h after termination of the chronic drug treatment. Ascending doses of intrathecal morphine were given every 30 min and the antinocieptive response was measured in the paw-pressure test 25 min after each injection. Significant differences from the action of morphine alone: ^*P<0.05, ^**P<0.01. CTAP, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂; CTOP, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂; NTI, naltrindole.

Figure 5

Effects of ultralow doses of opioid receptor antagonists on established morphine tolerance in the tail-flick test. (a) Time course of the effects of intrathecal CTOP (0.01 ng), CTAP (0.001 ng) and naltrindole (NTI; 0.01 ng) on established morphine tolerance in the tail-flick test. Tolerance was induced by single daily intrathecal injection of morphine (Mor; 15 μg) for 5 days. On day 6, morphine was administered with CTOP, CTAP or NTI as single injection until day 10. Nociceptive testing was performed 60 min after each injection. The data are expressed as mean±s.e.m. for four to five animals. (b) Cumulative dose–response curves for the antinociceptive effects of acute morphine in the treatment groups represented in (a). The dose–response curves were obtained 24 h after termination of the chronic drug treatment. Ascending doses of intrathecal morphine were given every 30 min and the antinocieptive response was measured in the tail-flick test 25 min after each injection. Significant differences from the action of morphine alone: ^*P<0.01, ^**P<0.001. CTAP, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂; CTOP, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂; NTI, naltrindole.

Figure 6

Effects of ultralow doses of opioid receptor antagonists on established morphine tolerance in the paw-pressure test. (a) Time course of the effects of intrathecal CTOP (0.01 ng), CTAP (0.001 ng) and naltrindole (NTI; 0.01 ng) on established morphine tolerance in the paw-pressure test. Tolerance was induced by single daily intrathecal injection of morphine (Mor; 15 μg) for 5 days. On day 6, morphine was administered with CTOP, CTAP or NTI as single injection until day 10. Nociceptive testing was performed 60 min after each injection. The data are expressed as mean±s.e.m. for four to five animals. (b) Cumulative dose–response curves for the antinociceptive effects of acute morphine in the treatment groups represented in (a). The dose–response curves were obtained 24 h after termination of the chronic drug treatment. Ascending doses of intrathecal morphine were given every 30 min and the antinocieptive response was measured in the paw-pressure test 25 min after each injection. Significant differences from the action of morphine alone: ^*P<0.01, ^**P<0.001. CTAP, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂; CTOP, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂; NTI, naltrindole.