Editorial Views  |   May 2006
Perspectives on the Genetic Basis of Opioid-induced Hyperalgesia
Author Affiliations & Notes
  • Andrea Nackley, Ph.D.
  • Luda Diatchenko, M.D., Ph.D.
  • William Maixner, D.D.S., Ph.D.
  • *Center for Neurosensory Disorders, University of North Carolina at Chapel Hill, School of Dentistry, Chapel Hill, North Carolina.
Article Information
Editorial Views / Central and Peripheral Nervous Systems / Pain Medicine / Pharmacology
Editorial Views   |   May 2006
Perspectives on the Genetic Basis of Opioid-induced Hyperalgesia
Anesthesiology 5 2006, Vol.104, 909-910. doi:
Anesthesiology 5 2006, Vol.104, 909-910. doi:
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.  1 evaluated 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,2,3 the 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.4–6 However, 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.  7,8 provided substantial pharmacologic and behavioral evidence that the stimulation of peripheral ADRB2s produces a hyperalgesic state in rats. Diatchenko et al.  9 recently 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.10 Furthermore, reductions in catechol-O  -methyl transferase activity enhance pain sensitivity in animal models via  the activation of β-adrenergic receptors.11 Therefore, 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, 13 Thus, 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.
Liang D-Y, Liao G, Wang J, Usuka J, Guo YY, Peltz G, Clark JD: A genetic analysis of opioid-induced hyperalgesia in mice. Anesthesiology 2006; 104:1054–62Liang, D-Y Liao, G Wang, J Usuka, J Guo, YY Peltz, G Clark, JD
Moises HC, Smith CB: Changes occur in central adrenoreceptor function following long-term morphine treatment and during morphine withdrawal. Neuropeptides 1984; 5:29–32Moises, HC Smith, CB
Ammer H, Schulz R: Chronic morphine treatment increases stimulatory beta-2 adrenoceptor signaling in A431 cells stably expressing the mu opioid receptor. J Pharmacol Exp Ther 1997; 280:512–20Ammer, H Schulz, R
Vanderah TW, Suenaga NM, Ossipov MH, Malan TP Jr, Lai J, Porreca F: Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance. J Neurosci 2001; 21:279–86Vanderah, TW Suenaga, NM Ossipov, MH Malan, TP Lai, J Porreca, F
Mao J, Sung B, Ji RR, Lim G: Chronic morphine induces downregulation of spinal glutamate transporters: Implications in morphine tolerance and abnormal pain sensitivity. J Neurosci 2002; 22:8312–23Mao, J Sung, B Ji, RR Lim, G
Li X, Clark JD: Hyperalgesia during opioid abstinence: Mediation by glutamate and substance P. Anesth Analg 2002; 95:979–84Li, X Clark, JD
Khasar SG, Green PG, Miao FJ, Levine JD: Vagal modulation of nociception is mediated by adrenomedullary epinephrine in the rat. Eur J Neurosci 2003; 17:909–15Khasar, SG Green, PG Miao, FJ Levine, JD
Khasar SG, McCarter G, Levine JD: Epinephrine produces a beta-adrenergic receptor-mediated mechanical hyperalgesia and in vitro  sensitization of rat nociceptors. J Neurophysiol 1999; 81:1104–12Khasar, SG McCarter, G Levine, JD
Diatchenko L, Anderson AD, Slade GD, Fillingim RB, Shabalina SA, Higgins T, Sama S, Belfer I, Goldman D, Max MB, Weir BS, Maixner W: Three major haplotypes of the β2adrenergic receptor define psychological profile, blood pressure, and the risk for development of a common musculoskeletal pain disorder. Am J Med Genet B Neuropsychiatr Genet 2006; (in press)
Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W: Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 2005; 135–43Diatchenko, L Slade, GD Nackley, AG Bhalang, K Sigurdsson, A Belfer, I Goldman, D Xu, K Shabalina, SA Shagin, D Max, MB Makarov, SS Maixner, W
Nackley AG, Lambert BL, Faison JM, Fecho K, Daitchenko L, Maixner W: Catechol-O-methyltransferase inhibition produces enhanced pain sensitivity and cytokine production via  a β-adrenergic mechanism. Presented at: International Association for the Study of Pain, 11th World Congress on Pain; August 25, 2005; Sydney, Australia
Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K, Arnold K, Ruano G, Liggett SB: Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo  responsiveness. Proc Natl Acad Sci U S A 2000; 97:10483–8Drysdale, CM McGraw, DW Stack, CB Stephens, JC Judson, RS Nandabalan, K Arnold, K Ruano, G Liggett, SB
Small KM, McGraw DW, Liggett SB: Pharmacology and physiology of human adrenergic receptor polymorphisms. Annu Rev Pharmacol Toxicol 2003; 43:381–411Small, KM McGraw, DW Liggett, SB