Paradoxical Effects of the Opioid Antagonist Naltrexone on Morphine Analgesia, Tolerance, and Reward in Rats

Abstract

Opioid agonists such as morphine have been found to exert excitatory and inhibitory receptor-mediated effects at low and high doses, respectively. Ultra-low doses of opioid antagonists (naloxone and naltrexone), which selectively inhibit the excitatory effects, have been reported to augment systemic morphine analgesia and inhibit the development of tolerance/physical dependence. This study investigated the site of action of the paradoxical effects of naltrexone and the generality of this effect. The potential of ultra-low doses of naltrexone to influence morphine-induced analgesia was investigated in tests of nociception. Administration of intrathecal (0.05 and 0.1 ng) or systemic (10 ng/kg i.p.) naltrexone augmented the antinociception produced by an acute submaximal dose of intrathecal (5 g) or systemic (7.5 mg/kg i.p.) morphine in the tail-flick test. Chronic intrathecal (0.005 and 0.05 ng) or systemic (10 ng/kg) naltrexone combined with morphine (15 g i.t.; 15 mg/kg i.p.) over a 7-day period inhibited the decline in morphine antinociception and prevented the loss of morphine potency. In animals rendered tolerant to intrathecal (15 g) or systemic (15 mg/kg) morphine, administration of naltrexone (0.05 ng i.t.; 10 and 50 ng/kg i.p.) significantly restored the antinociceptive effect and potency of morphine. Thus, in ultra-low doses, naltrexone paradoxically enhances morphine analgesia and inhibits or reverses tolerance through a spinal action. The potential of naltrexone to influence morphine-induced reward was also investigated using a place preference paradigm. Systemic administration of ultra-low doses of naltrexone (16.7, 20.0, and 25.0 ng/kg) with morphine (1.0 mg/kg) extended the duration of the morphine-induced conditioned place preference. These effects of naltrexone on morphine-induced reward may have implications for chronic treatment with agonist-antagonist combinations.Opioid drugs such as morphine are widely used in the treatment of severe pain; however, their chronic administration results in the development of tolerance to their analgesic effects, limiting their clinical usefulness in pain management. Although the mechanisms underlying the development of opioid tolerance are poorly understood, recent studies have suggested that alterations in the coupling of opioid receptors to G protein-linked effectors may play a significant role (Crain and Shen, 2000). Morphine and related agonists are recognized to produce their characteristic acute and chronic effects by activating spinal and supraspinal -, ␦-, and -opioid receptors. Classically, morphine activates G i protein-coupled -opioid receptors to inhibit adenylyl cyclase activity and decrease neuronal cAMP levels (Uhl et al., 1994). At the presynaptic level, -opioid receptor activation inhibits voltage-sensitive Ca 2ϩ channels (Tallent et al., 1994) and reduces neurotransmitter release, whereas at the postsynaptic level, it opens potassium channels and hyperpolarizes neurons (North and Williams, 1983;Ikeda et al., 1995). The net result of th...

Ultra-Low-Dose Naloxone Restores the Antinociceptive Effect of Morphine and Suppresses Spinal Neuroinflammation in PTX-Treated Rats

“…Co-administration or post-treatment with an ultralow dose of naltrexone or naloxone was found to potentiate the antinociceptive effect of morphine on the neuropathic thermal hyperalgesia in rats (Powell et al, 2002), and extends the duration of analgesia in morphine-tolerant rats (Powell et al, 2002;Wang et al, 2005). The mechanism has been hypothesized to be due to the inhibition of the excitatory signaling of opioid receptors (Shen and Crain, 1997).…”

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

“…73 Interestingly, the doses of NTX used in this study are 10-to 100-fold higher than the NTX doses shown to enhance analgesia and prevent tolerance in intact animals yet 100-fold to 1000-fold lower than doses used to block opioid analgesia via MORs. 25,35,50,56,74,84 Although we believe this to be the first study to assess oral delivery of an ultra-low-dose opioid antagonist in animals, a direct comparison with intrathecal NTX was possible with the study by Powell et al 56 The multitude of neuroplastic changes underlying neuropathic pain, including the extent of MOR-G s coupling now thought to be controlled by filamin A, 73 may contribute to the need for somewhat higher doses of NTX in alleviating hypersensitivities in nerve-injured animals compared with NTX doses reported to enhance opioid analgesia in intact rodents.In conclusion, the present work demonstrates that SNL injury, like chronic opioid treatment, induces G s coupling by MOR. This aberrant signaling may contribute to the excitatory neurotransmission in spinal dorsal horn after neuropathic injury as well as to the decreased efficacy of endogenous and exogenous MOR agonists in alleviating neuropathic pain.…”

Naloxone attenuates incubated sucrose craving in rats

“…As the effects of opiate antagonism on conditioned reward, let alone incubation of reward craving, have not as yet been extensively characterized, we selected a broad dose range for our study. Previous researchers (Glass et al 1999;Ciccocioppo et al 2002;Colantuoni et al 2002;Powell et al 2002;Pickering and Liljequist 2003;D'Anci and Kanarek 2004;Leri and Burns 2005;Olmstead and Burns 2005) have described behaviorally relevant effects of naloxone and the similar naltrexone in the ultralow (down to 1 pg/kg), very low (30 ng/kg), and moderate (1-5 mg/kg) to relatively high dose range (up to 20 mg/kg). We chose doses in the submoderate to high range as doses into the very low/ultralow range may antagonize by nonclassic (non receptor-blocking) mechanisms (Olmstead and Burns 2005).…”