Tolerance with agonist-antagonist opioids

The treatment of opioid abuse and dependence aims also at preventing the social complications of abuse, especially infections linked to parenteral administration (HIV and HepB). It relies on the use of substimtive drugs that can be either pure agonists, or partial agonist-antagonists (methadone, buprenor-phine, naltrexone), with the objective of limiting receptor desensitization and the development of tolerance. Any success in the treatment of opiate dependence may stem as much from the re-establishment of healthcare contact and social reinsertion as from any treatment induced decrease in the abuse behaviour itself. 

Constriction of the pupils is seen with virtually all opioid agonists. Miosis is a pharmacologic action to which little or no tolerance develops (Table 31-3) thus, it is valuable in the diagnosis of opioid overdose. Even in highly tolerant addicts, miosis is seen. This action, which can be blocked by opioid antagonists, is mediated by parasympathetic pathways, which, in turn, can be blocked by atropine. 

The concurrent use of two opioid agonists may have enhanced effects, although acute opioid tolerance may also occur. Opioids with mixed agonist/antagonist properties (e.g. buprenorphine, butorphanol, nalbuphine, pentazocine) may precipitate opioid withdrawal symptoms in patients taking pure opioid agonists (e.g. fentanyl, methadone, morphine). 

The three prototype mixed p agonist/S antagonists described in this chapter have excellent potential as analgesics with low propensity to produce tolerance and dependence. The pseudotetrapeptide DIPP-NH2[ ] has already been shown to produce a potent analgesic effect, less tolerance than morphine, and no physical dependence upon chronic administration. In preliminary experiments, the tetrapeptides DIPP-NH2 and DIPP-NH2[T] were shown to cross the BBB to some extent, but further structural modifications need to be performed in order to improve the BBB penetration of these compounds. The Tyr-Tic dipeptide derivatives can also be expected to penetrate into the central nervous system because they are relatively small, lipophilic molecules. In this context, it is of interest to point out that the structurally related dipeptide H-Dmt-D-Ala-NH-(CH2)3-Ph (SC-39566), a plain p-opioid agonist, produced antinociception in the rat by subcutaneous and oral administration [72], As indicated by the results of the NMR and molecular mechanics studies, the conformation of the cyclic p-casomorphin analogue H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] is stabilized by intramolecular hydrogen bonds. There-... 

Opioids also interact with excitatory amino acid neurotransmitters. At lower micromolar concentrations, p agonists (e.g., DAMGO) enhance NMDA activity in the nucleus accumbens, but inhibit non-NMDA activity (Martin et al. 1997). At higher concentrations (5 pM), NMDA currents are reduced. Conversely, central administration of glutamate can precipitate a withdrawal syndrome in morphine-dependent animals, similar to the opioid antagonist naloxone. NMDA mechanisms also appear to be involved in the development of morphine tolerance. Competitive and noncompetitive NMDA antagonists and inhibitors of nitric oxide synthase reduce or eliminate tolerance to morphine (Elliott et al. 1995 Bilsky et al. 1996). However, this does not occur for tolerance to k opioids. Pharmacokinetics... 

The novel use of J-receptor antagonists with M-receptor agonists is also emerging as a strategy to avoid the development of tolerance. This idea has developed around the observation that mice lacking the J-opioid receptor fail to develop tolerance to morphine. 

The development of acute tolerance and dependence evoked in mice by morphine can be suppressed by pretreatment with NTI. Multiple administration of either NTI or 5 NTII before and during chronic implantation with morphine pellets also substantially inhibits the development of morphine tolerance and dependence. These results suggest the use of 8 antagonists to be useful for the prevention of opioid tolerance and physical dependence without compromising the antinociceptive potency of p opioid receptor agonists (Abdelhamid et al., 1991). 

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