Morphine Tolerance in Spinal Cord Is Due to Interaction between μ- and δ-Receptors

Abstract

When the opioid agonist morphine is given chronically and systemically to mice by pellet implantation for 3 days, the animals develop substantial tolerance to the antinociceptive effect of a test dose of morphine given systemically. When the test dose is administered to the spinal cord, however, very little tolerance is observed. We tested six strains of mice differing in the degree to which they develop systemic tolerance to morphine and found that none of them developed significant tolerance to spinal morphine. However, most of these strains did develop substantial spinal tolerance to antinociception induced by the selective -ag- ]-enkephalin (DPDPE). Moreover, in naïve animals, the antinociceptive effect of both DAMGO and DPDPE was blocked by D-Phe-Cys-Tyr-D-Trp-Arg-Thr-PenThr-NH 2 , a selective -antagonist, indicating that both agonists mediate antinociception in the spinal cord through -receptors. In addition to directly mediating antinociception, however, DPDPE potentiated the antinociceptive activity of DAMGO in the spinal cord of naïve animals, and this antinociception was blocked by the ␦-antagonist H-TyrTicPsi[CH 2 NH]Phe-Thr-OH (TIPP), indicating mediation through ␦-receptors. In contrast, in tolerant animals, TIPP enhanced the antinociception of DAMGO. These results thus demonstrate not only that -and ␦-opioid receptors interact in naïve animals, but that the nature of this interaction changes during tolerance, from a potentiation to an inhibition. The lack of tolerance to spinal morphine may result from the ability of morphine to act as a partial antagonist at ␦-receptors.There are three major types of opioid receptors in the mammalian central nervous system, , ␦, and , encoded by distinct, although homologous genes (Satoh and Minami, 1995), and they differ in sensitivity to agonists. A preponderance of evidence indicates that opioid antinociception is mediated via the -receptor (Fang et al., 1986;Matthes et al., 1996;Sora et al., 1997), although ␦-and -receptors can also mediate this effect in at least some central nervous system locations and some antinociceptive tests Qi et al., 1990;Sofuoglu et al., 1991). However, several lines of evidence suggest that interactions among different types of opioid receptors may also contribute to the pharmacology of these drugs. This evidence is both pharmacological and biochemical. Pharmacologically, it has been shown that activation of one opioid receptor type can alter the sensitivity to agonist of a different receptor type in the same location, or of the same receptor type in a different location. Examples of the first type of interaction include potentiation of -receptor agonist-induced antinociception by ␦-receptor agonist in the brain (Heyman et al., , 1989 or spinal cord (Larson et al., 1980;He and Lee, 1998). Examples of the second type of effect include synergistic (mutually potentiating) effects of -agonists in the brain and spinal cord or between different regions in the brain (Yeung and Rudy, 1980;Roerig et al., 1984;Bodnar et al., 1991;Ros...

Essential role of mu opioid receptor in the regulation of delta opioid receptor–mediated antihyperalgesia

“…More studies will be needed to show whether or not endogenous opioids and MOR activation are required for the regulation of DOR during persistent inflammation. For instance, the fact that CTOP does not significantly influence the effect of deltorphin II suggests that acute activation of MOR or its occupancy by an antagonist is not involved in the regulation of DOR, which is somehow in contrast with reports from others (He and Lee, 1998, Gomes et al, 2000, Riba et al, 2002.…”

Tolerance develops in spinal cord, but not in brain with chronic [Dmt1]DALDA treatment

“…This contrasts with a degree of tolerance of less than 10-fold when DAMGO (i.t.) was administered to animals made tolerant to morphine (Riba et al, 2002b). Again, in the latter study, morphine was administered chronically by pellet implantation, which should have maximized the degree of tolerance developed.…”

“…In contrast, in morphinetolerant animals, tolerance to DAMGO (i.t.) was only 4-5-fold (Riba et al, 2002b Tables 2 (brain) and 3 (spinal cord). In brain, the expression levels of MOR and DOR were significantly altered in [Dmt 1 ]DALDA-treated mice relative to controls, at the Po0.01 level, while those of PE and PD were altered significantly at Po0.05.…”

Role of NK-1 neurotransmission in opioid-induced hyperalgesia

“…Control groups receive the same number of placebo pellets. The morphine and placebo pellets were a generous gift of the National Institute on Drug Abuse (NIDA) and their use and doses in rats (two pellets) and mice (one pellet) were carried out according to standard methods (Gardell et al, 2002;Gold et al, 1994;Riba et al, 2002;Schmidt et al, 2002;Smith et al, 1999Smith et al, , 2002Vanderah et al, 2001b;Yoburn et al, 1985). Previous studies have shown that implantation of two morphine pellets (75 mg, free base) results in a steady state of plasma morphine levels by 3 days post-pellet implant, ranging between 86.8±13.1 and 156±45 ng/ml, that was maintained through 12 days post-pellet implant (Gold et al, 1994;Yoburn et al, 1985).…”