Inhibition of tolerance to spinal morphine antinociception by low doses of opioid receptor antagonists

Ultra-low doses of opioid receptor antagonists inhibit development of chronic spinal morphine tolerance. As this phenomenon mechanistically resembles acute tolerance, the present study examined actions of opioid receptor antagonists on acute spinal morphine tolerance. In adult rats, administration of three intrathecal injections of morphine (15 μg) at 90 min intervals produced a significant decline of the antinociceptive effect and loss of agonist potency in both the tail-flick and paw-pressure tests. These reduced responses, indicative of acute tolerance, were blocked by co-injection of morphine (15 μg) with naltrexone (NTX, 0.05 ng), D–Phe–Cys–Tyr–D–Trp–Orn–Thr–Pen–Thr–NH2 (CTAP, 0.001 ng), naltrindole (0.06 ng), or nor-binaltorphimine (0.1 ng). Repeated injections of CTAP, naltrindole, or nor-binaltorphimine without morphine elicited a delayed weak antinociceptive response which was blocked by a high dose of naltrexone (2 μg). In another set of experiments, administration of low dose spinal (0.05 ng) or systemic (0.01 μg/kg) morphine produced a sustained thermal hyperalgesia. This response was blocked by opioid receptor antagonists at doses inhibiting development of acute morphine tolerance. Lastly, an acute spinal injection of morphine (15 μg) with naltrexone (0.05 ng) produced a sustained analgesic response; this was antagonized by adenosine receptor antagonist, 8-phenyltheophylline (3 μg). The results show that ultra-low doses of opioid receptor antagonists block acute tolerance to morphine. This effect may result from blockade of opioid excitatory effects that produce a latent hyperalgesia that then contributes to induction of tolerance. The sustained antinociception produced by combination of morphine with an opioid receptor antagonist shows dependency on the adenosine receptor activity.