Opioids are effective analgesics for the management of moderate to severe cancer pain. Here we show that κ opioid receptor (KOR) agonists act as anti-angiogenic factors in tumors. Treatment with KOR agonists, U50,488H and TRK820, significantly inhibited human umbilical vein endothelial cell (HUVEC) migration and tube formation by suppressing VEGFR2 expression. In contrast, treatment with a μ opioid receptor agonist, DAMGO, or a δ opioid receptor agonist, SNC80, did not prevent angiogenesis in HUVECs. Lewis lung carcinoma (LLC) or B16 melanoma grafted in KOR knockout mice showed increased proliferation and remarkably enhanced tumor angiogenesis compared with those in wild type mice. On the other hand, repeated intraperitoneal injection of TRK820 (0.1–10 μg/kg, b.i.d.) significantly inhibited tumor growth by suppressing tumor angiogenesis. These findings indicate that KOR agonists play an important role in tumor angiogenesis and this knowledge could lead to a novel strategy for cancer therapy.

The opioid system (opioid peptides and receptors) regulates a variety of neurophysiologic functions, including pain control. Here we show novel roles of the opioid system in vascular development. IntroductionOpioids are defined by their ability to bind to and influence opioid receptors on cell membranes. Three opioid receptors, , ␦, and (MOR, DOR, and KOR), are inhibitory G (Gi) protein-coupled receptors through which endogenous opioids (endorphins, enkephalins, and dynorphins) regulate physiologic functions, such as pain regulation, emotional tone, and reward circuitry. 1 These opioid receptors are the principle physiologic target for most clinically important opioid analgesics, such as morphine. Opioid systems are mainly present in neural tissue and could be involved in neurogenesis during brain development. 2,3 We previously showed that DOR, but not MOR or KOR, plays a crucial role in neurogenesis and neuroprotection in neural stem cells obtained from embryonic C3H mouse forebrain. 4 In recent studies that used embryonic stem (ES) cells, MOR and KOR were shown to promote neural progenitor differentiation and regulate cell specification from neural progenitors. 5,6 Moreover, KOR is highly expressed in human neural precursor cells and functions during neurogenesis in the fetal brain. 7 These results indicate that the opioid systems are involved in neurogenesis from neural stem and progenitor cells.Although endogenous opioids were first characterized in the brain, these opioid systems are found both in neural (brain and spinal cord) and extraneural tissues (ganglia, gut, spleen, stomach, lung, pancreas, liver, heart, blood, and blood vessels). Opioids and opioid receptors were reported to exist in blood vessels in the later stage rat embryo (embryonic day [E]Ϫ16) through adult. 8,9 The addition of opioid peptides inhibited angiogenesis in a chick chorioallantoic membrane model 10 and DNA synthesis in rat vascular walls. 8 In the adult, the endogenous opioid system has been shown to be active in hemodynamic and cardiovascular responses, such as hemorrhagic shock, sepsis, and trauma. 11 The selective opioid receptor agonist U-50,488H has beneficial effects on vascular injury after spinal cord trauma by improving vascular permeability and edema. 12 These findings suggest that the opioid system plays an important role in vascular functions though its physiologic roles and molecular mechanisms remain largely unknown.VEGF/VEGF receptor-2 (fetal liver kinase 1; Flk1) signaling is a key regulator of vascular development during embryogenesis. A VEGF coreceptor, Neuropilin1 (NRP1), is largely coexpressed with Flk1 in vascular progenitors and forms a specific and sensitive receptor for VEGF 164 , an isoform of VEGF. 13,14 The Flk1-VEGF 164 -NRP1 complex potently enhances Flk1 signaling in vascular development. 13 NRP1 is also expressed in particular classes of developing neurons and functions as a receptor for class 3 semaphorins by forming a heterodimer with plexins. [15][16][17] PlexinD1 and semaphorin regulate not onl...

No abstract

Both the up-regulation of substance P and down-regulation of μ-opioid receptor seen in the dorsal root ganglia may be, at least in part, responsible for the abdominal pain-like state associated with peritoneal carcinomatosis.

No abstract

Although the way for pain management associated with acute pancreatitis has been searched for, there are not enough medications available for it. The aim of the present study was to investigate the role of bradykinin (BK) in pain related to acute pancreatitis. After repeated injections of caerulein (50 μg/kg and 6 times), mice showed edema in the pancreas, and blood concentrations of pancreatic enzymes (amylase and lipase) were clearly elevated. A histopathological study demonstrated that caerulein caused tissue damage characterized by edema, acinar cell necrosis, interstitial hemorrhage, and inflammatory cell infiltrates. Furthermore, the mRNA levels of interleukin-1β and monocyte chemotactic protein (MCP)-1 were significantly increased in the pancreas of caerulein-treated mice. The sensitivity of abdominal organs as measured by abdominal balloon distension was enhanced in caerulein-injected mice, suggesting that caerulein caused pancreatic hyperalgesia. Moreover, repeated treatment with caerulein resulted in cutaneous tactile allodynia of the upper abdominal region as demonstrated by the use of von Frey filaments, indicating that caerulein-treated mice exhibited referred pain. Under this condition, the mRNA levels of bradykinin B1 receptor (BKB1R) and bradykinin B2 receptor (BKB2R) were significantly increased in the dorsal root ganglion (DRG). Finally, we found that des-Arg⁹-(Leu⁸)-bradykinin (BKB1R antagonist) and HOE-140 (BKB2R antagonist) attenuated the acute pancreatitis pain-like state in caerulein-treated mice. These findings suggest that the upregulation of BK receptors in the DRG may, at least in part, contribute to the development of the acute pancreatitis pain-like state in mice.

Vagal nerves modulate not only physical homeostasis, but also pain transmission. It has been reported that subdiaphragmatic vagal dysfunction causes visceral pain. However, the functional changes in nociceptive primary afferent fibers under such visceral pain soon after subdiaphragmatic vagal dysfunction are not fully documented. The present study was designed to investigate changes in the sensitivity of primary afferent fibers in the distal colon using a Neurometer which individually stimulates C, Aδ and Aβ fibers. Under stimulation with a handmade stimulus electrode in the distal colon, the current threshold in the distal colon was recorded with high reproducibility. Subdiaphragmatic vagotomy significantly decreased the current threshold of Aδ fibers in the distal colon with no change in the sensitivity of C or Aβ fibers. These results suggest that vagal dysfunction at an early stage may cause, at least in part, hypersensitivity of visceral Aδ fibers.

No abstract