Mechanisms of Opioid-Induced Tolerance and Hyperalgesia

Anna DuPen, MN, ARNP; * Danny Shen, PhD; ‡ Mary Ersek, PhD, RN†


Pain Manag Nurs. 2007;8(3):113-121. 

In This Article

Opioid Receptor Physiology

A discussion of opioid tolerance is best prefaced with a review of opioid receptor physiology. Researchers have identified three types of opioid receptors: mu, delta, and kappa receptors. These receptors are distributed in various locations within the spinal cord and brain structures. Figure 1 shows the distribution of opioid receptors in the brain of a guinea pig. Mu opioid receptors are highly concentrated in the outer laminae of the dorsal horn of the spinal cord, whereas delta opioid receptors are diffusely distributed throughout the dorsal horn (Quirion 1984, Quirion et al 1983). Kappa opioid receptors are concentrated in the outer laminae of the dorsal horn of the lumbosacral cord and are closely associated with neural input from the visceral structures (Quirion 1984, Quirion et al 1983). Two areas of the brainstem—the rostral ventromedial medulla (RVM) and the periaqueductal gray (PAG)—express high levels of mu opioid receptors; delta and kappa receptors are also expressed, albeit at much lower levels (Mansour et al 1987, Mansour et al 1995). Studies have demonstrated mu and some delta opioid receptors on neurons that arise from the PAG or RVM and descend to the spinal cord where they inhibit pain transmission (Van Bockstaele et al., 1996).

Image of guinea pig brain; red areas represent highest density, yellow areas represent moderate density, and blue, purple, and white represent low density of opioid receptors. Reprinted with permission from Solomon H. Snyder, MD, Department of Neuroscience, Johns Hopkins Medical School.

Clinically available and experimental opioids have differing potency and efficacy at the various opioid receptors. The overall action of a particular opioid is the sum effect of activation of all the relevant receptors. Most of the opioids that are currently used in clinical practice are predominantly mu agonists (although some also bind at delta or kappa receptors or both). There are at least seven "subtypes" of the mu receptor (Pasternak, 2001), and each opioid may have different affinities for the various mu receptor subtypes. Tolerance may develop separately at each mu receptor subtype in response to a particular opioid. When a patient is switched from one opioid to another, the "new" opioid may have a different selectivity for the individual mu receptor subtypes, which explains "incomplete" cross-tolerance and offers a way to overcome tolerance.

This difference in how opioids interact with the mu receptor subtypes and/or their ability to activate the other opioid receptor types could explain or predict clinical differences in the pharmacologic effect of one opioid compared with another. Moulin et al. (1988) studied tolerance in morphine versus levorphanol, an opioid that is active at all three opioid receptors. Pretreatment with levorphanol in rats caused tolerance to morphine and levorphanol, but pretreatment with morphine caused tolerance only to morphine and not to levorphanol, indicating that receptor selectivity influences tolerance (Moulin et al., 1988). More recently, investigators have postulated that the ability of methadone to differentially activate delta opioid receptors may be a contributing factor to its incomplete cross-tolerance in patients who had become tolerant to mu opioids such as morphine (Lynch, 2005).

Some investigators have postulated that genetic variations in receptors, often referred to as genetic polymorphism, can account for interindividual differences in pain sensitivity, opioid analgesic response, and risk of psychologic dependence (Bond et al 1998, Estfan et al 2005, Thomsen et al 1999). Approximately 500 genes have been identified that influence pain in animal and human studies, with about 100 variations in the human mu opioid receptor gene alone (Ross et al., 2006). At present, the functional significance of many of these pain-related and opioid receptor genetic variants has not been fully elucidated. For example, the A118G genetic variant of the mu opioid receptor, which results in a change in amino acids from asparagine to aspartate at position 40, has been studied in both pain (Hirota et al 2003, Lotsch et al 2002, Lotsch et al 2002, Ross et al 2005) and addiction (Bergen et al 1997, Bond et al 1998, Li et al 2000, Sander et al 1998, Town et al 1999), with conflicting reports on its relationship to morphine potency or its association with risk of substance abuse. A recent study explored the influence of variations in genes that encode the mu opioid receptor and its regulatory proteins on opioid response in a cancer patient population. There were no significant differences in the frequency of several variants of mu opioid receptor genes between patients responsive to morphine and those intolerant of morphine. There were, however, significant differences in frequency of two genetic variants (i.e., stat6, mu opioid gene transcriptional factor; and -arrestin2, intracellular regulatory protein) between patients who required a switch from morphine to an alternative opioid compared with those who obtained adequate analgesia with morphine (Ross et al., 2005). These differences suggest that genetic variations among individuals influence clinical responses to morphine and possibly other opioids.


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