OPIOID analgesics represent one of the few classes of pharmacologic agents used to treat persistent pain conditions. In this issue of Anesthesiology, Liang et al. 1evaluated the pain-promoting effects of repeated doses of opioids in 15 strains of inbred mice. As noted by the authors, there is increasing recognition that acute and chronic opioid use can result in opioid-induced hyperalgesia (OIH), a syndrome characterized by increased sensitivity to noxious stimuli and increased clinical pain report. The clinical observation that only a subset of individuals is susceptible to this phenomenon strongly suggests a genetic influence. Furthermore, the observation that OIH is more common in patients with a history of opioid abuse suggests that OIH and opioid abuse may share common underlying genetic and neurobiologic mechanisms. The results of the current study are potentially of substantial clinical relevance because they directly illustrate the importance of β2-adrenergic receptor (ADRB2) in mediating OIH.
The authors used newly developed in silico murine genetic approaches to provide evidence that ADRB2 stimulation induces a hyperalgesic state that contributes to OIH. They demonstrated that in silico genetic analyses, coupled with pharmacologic experiments, provide an extremely powerful approach for the dissection of genetic factors and biologic pathways that contribute to complex pain behaviors, traits, and phenotypes. The use and further development of these methodologies promise to accelerate our understanding of the underlying processes that contribute to pathologic pain states as well as the pharmacologic actions of opioids and other analgesics.
Although there is evidence that opioid receptor stimulation increases the expression of ADRB2s,2,3the identified functional role of ADRB2 s in OIH is a novel and unexpected finding. Previous studies have identified brain and spinal cord facilitatory mechanisms in the genesis of OIH.4–6However, there is growing evidence that peripherally located ADRB2s contribute to both basal pain sensitivity and the development of persistent pain states. For example, Khasar et al. 7,8provided substantial pharmacologic and behavioral evidence that the stimulation of peripheral ADRB2s produces a hyperalgesic state in rats. Diatchenko et al. 9recently reported that the three major haplotypes of the human ADRB2 are strongly associated with the risk of developing a common human chronic pain condition, temporomandibular joint disorder. Consistent with these observations, recent studies have shown that decreased activity of catechol-O -methyl transferase (an enzyme that regulates the bioavailability of the endogenous ADRB2 agonist epinephrine) is associated with enhanced sensitivity to pain and the risk of temporomandibular joint disorder.10Furthermore, reductions in catechol-O -methyl transferase activity enhance pain sensitivity in animal models via the activation of β-adrenergic receptors.11Therefore, the outcomes of the current study have identified a new mechanism whereby the ADRB2 contributes to heightened pain states.
The outcomes of this study also point the way to several future studies. Although the association between ADRB2 haplotypes and OIH is clear, the specific biologic mechanisms that contribute to this association remain to be elucidated. In humans, the three common ADRB2 haplotypes differ with respect to signaling properties, expression, and agonist-induced internalization. 9,12, 13Thus, the finding that ADRB2s mediate OIH in a strain- and haplotype-specific manner in mice suggests that the capacity of ADRB2s to mediate OIH in humans is also genotype specific. Therefore, human association studies that examine the relationship between genetic variants of ADRB2 and clinically observed OIH are required. It is also highly probable that other genes and associated proteins will have an equal or greater influence on OIH. The authors note that only a small fraction of murine genes have been optimally resolved. As the information in the murine and human genomic databases expands, it is highly likely that many more genes and biologic pathways will be identified that contribute to OIH and persistent pain states.
The current findings have important clinical implications, suggesting that ADRB2 antagonists will be effective in attenuating OIH and in treating a variety of other persistent pain conditions. Furthermore, the findings suggest that genotyping will prove useful in identifying (1) responders and nonresponders to opioid analgesics, (2) individuals at risk for developing persistent pain conditions, and (3) novel pharmacologic strategies for treating persistent pain conditions. We await the outcomes of studies that examine the clinical significance of these intriguing findings.
*Center for Neurosensory Disorders, University of North Carolina at Chapel Hill, School of Dentistry, Chapel Hill, North Carolina. bill_maixner@dentistry.unc.edu
