Known unknowns: A review of opioid-induced hyperalgesia

Opioid-induced hyperalgesia (OIH) is a relatively new paradigm that has added to the already growing uncertainty surrounding long-term opioid treatment. OIH is the oversensitization to stimuli in the nervous system resulting from opioid exposure and subsequent neuroplastic changes. Because of its novelty and difficulty in identification, the true prevalence of OIH is unknown. Several mechanisms have been proposed for its development. These include changes in the N-methyl-D-aspartate system, descending pathway modulation, dynorphin activity, inflammatory changes mediated by cyclooxygenase, and increased sensitivity to excitatory neurochemicals. The clinical controversy regarding the management of OIH is due largely to the lack of guidance in diagnosis and lack of quality evidence to direct treatment. As a diagnosis of exclusion, several alternative causes of antianalgesia must be ruled out before OIH can be declared. Pharmacodynamic phenomena such as opioid tolerance share overlapping mechanisms with OIH and may present similarly. Pharmacokinetic changes such as drug-induced or disease-induced alterations to the cytochrome P450 or P-glycoprotein systems should also be excluded as causes of increased opioid demand that may be seen as OIH. Certain pharmacologic agents, such as N-methyl-D-aspartate receptor antagonists, alpha2 receptor agonists, and cyclooxygenase inhibitors, have been identified as possible treatments to reverse the effects of OIH. Opioid rotation and dose reductions have also been used with some degree of success. Pharmacist involvement in the identification and management of OIH will be central to success because of the unique expertise they offer. The quality of these studies is limited by study design, small sample sizes, and lack of generalizability to chronic pain patients with long-standing opioid use.

Differential Expression of Alpha2 Integrin In Human Bone Marrow and Cord Blood CD34+CD38- Progenitors and Stem Cells Reconstituting NOD/SCID-IL2Rgammacnull Mice.

Abstract 2609 Human primitive stem cells reside in the CD34+CD38- fraction in cord blood and bone marrow. However, there is a high level of heterogeneity in these cell fractions, and the phenotype of the rare primitive stem cells remains poorly defined. We have studied expression of integrin alpha2 chain, a member of a family of beta1 integrin cell adhesion receptors, in CD34+CD38- cells in adult bone marrow and cord blood. >90% of bone marrow CD34+CD38- cells and >95% of CD34+CD38-CD90+ cells, enriched in long-term in vivo reconstituting stem cells (Majeti et al., Cell Stem Cell 1:635, 2007) expressed the integrin alpha2 chain. In contrast, in cord blood CD34+CD38- and the CD34+CD38-CD90+ subpopulation, the integrin alpha2 chain was expressed only in 37.1+/− 5.3% and 32.2+/− 4.9% of the cells (mean+/− SD), respectively. To determine whether integrin alpha2 expression could be used to identify functionally distinct stem and progenitor cell populations in cord blood and bone marrow, we isolated CD34+CD38- integrin alpha2+ and alpha2- cells by flow cytometry and analyzed these by in vivo transplantation into immunodeficient NOD/SCID-IL2Rgammacnull (NSG) mice and by in vitro progenitor cell assays (long-term culture initiating cell, LTC-IC, and colony assays). Transplantation of cord blood CD34+CD38- integrin alpha2+ cells resulted in significantly higher level of human CD45+ (p<0.05), myeloid (p<0.01) and CD34+ (p<0.05) cell engraftment at 16–18 weeks after transplantation than integrin alpha2- cells (reconstitution/300 cells in age and sex matched recipients, Figure 1). In contrast, there were no differences in reconstitution at 12 weeks in mice transplanted with cord blood CD34+CD38- alpha2+ and alpha2- cells. Because of lower engraftment capacity of adult bone marrow cells in immunodeficient mice, bone marrow CD34+CD38- cells were analyzed after intra-bone transplantation. After 12 weeks only few mice transplanted with the CD34+CD38- integrin alpha2+ cells but none transplanted with the corresponding alpha2- cells were reconstituted with human CD45+ or myeloid cells at a level '0.1%. The LTC-IC progenitors within the CD34+CD38- populations, assayed after 6 weeks culture on stroma, in adult bone marrow were highly enriched in the alpha2+ as compared with alpha2- fraction (mean +/− SD 96.7+/− 57.0 and 0.2+/− 0.6 colonies/50 cells, respectively), whereas in cord blood they resided equally in both integrin alpha2+ and alpha2- cell fractions (mean +/− SD 77.4+/− 59.4 and 108.8+/− 96.0 colonies/50 cells, respectively). The lineage committed CFU-GM and BFU-E progenitors in adult bone marrow were within integrin CD34+CD38- alpha2+ and alpha2- fractions (mean +/− SD 8.5+/− 5.3 and 14.9+/− 16.2 colonies/100 cells, respectively), whereas in cord blood they were significantly enriched in the alpha2- fraction (mean +/− SD 9.3+/− 5.5 and 22.0+/− 6.7 colonies/100 cells in alpha2+ and alpha2- fractions, respectively). Taken together, our results show expression of integrin alpha2 receptor in most of the primitive cord blood long-term in vivo reconstituting stem cells, with a gradual loss of the integrin alpha2 receptor during maturation to short term in vivo reconstituting stem cells, LTC-IC and lineage committed progenitors. Furthermore, our findings show distinct ontogeny-related differences in the expression of the integrin alpha2 receptor in the functionally defined primitive and lineage-committed CD34+CD38- progenitors, indicating differences in cellular interactions of cord blood and bone marrow progenitors with the hematopoietic niches. Disclosures: Ekblom: Bristol-Myers Squibb: Honoraria.

Activation of α2B-Adrenoceptors Mediates the Cardiovascular Effects of Etomidate

Background The intravenous anesthetic etomidate exhibits structural similarities to specific alpha2-adrenoceptor agonists of the type such as dexmedetomidine. The current study was performed to elucidate the possible interaction of etomidate with alpha2-adrenoceptors in mice lacking individual alpha2-adrenoceptor subtypes (alpha2-KO). Methods Sedative and cardiovascular responses to etomidate and the alpha2-agonist, dexmedetomidine, were determined in mice deficient in alpha2-receptor subtypes. Inhibition of binding of the alpha2-receptor antagonist [3H]RX821002 to recombinant alpha2-receptors by etomidate was tested in human embryonic kidney (HEK293) cells in vitro. Results In vivo, loss and recovery of the righting reflex required similar times after intraperitoneal injection of etomidate in wild-type and in alpha2A-receptor-deficient mice, indicating that the hypnotic effect of etomidate in mice does not require the alpha2A-receptor subtype. Intravenous injection of etomidate resulted in a transient increase (duration 2.4 +/- 0.2 min) in arterial blood pressure in wild-type mice (17 +/- 3 mmHg). Etomidate did not affect blood pressure in alpha2B-KO or alpha2AB-KO mice. In membranes from HEK293 cells transfected with alpha2-receptors, etomidate inhibited binding of the alpha2-antagonist, [3H]RX821002, with higher potency from alpha2B- and alpha2C-receptors than from alpha2A-receptors (Ki alpha2A 208 microm, alpha2B 26 microm, alpha2C 56 microm). In alpha2B-receptor-expressing HEK293 cells, etomidate rapidly increased phosphorylation of the extracellular signal-related kinases ERK1/2. Conclusions These results indicate that etomidate acts as an agonist at alpha2-adrenoceptors, which appears in vivo primarily as an alpha2B-receptor-mediated increase in blood pressure. This effect of etomidate may contribute to the cardiovascular stability of patients after induction of anesthesia with etomidate.