Connective tissue growth factor (CTGF) is a novel cysteine-rich, secreted protein. Recently, we found that inhibition of the endogenous expression of CTGF by its antisense oligonucleotide and antisense RNA suppresses the proliferation and migration of vascular endothelial cells. In the present study, the following observations demonstrated the angiogenic function of CTGF in vitro and in vivo: (i) purified recombinant CTGF (rCTGF) promoted the adhesion, proliferation and migration of vascular endothelial cells in a dose-dependent manner under serum-free conditions, and these effects were inhibited by anti-CTGF antibodies; (ii) rCTGF markedly induced the tube formation of vascular endothelial cells, and this effect was stronger than that of basic fibroblast growth factor or vascular endothelial growth factor; (iii) application of rCTGF to the chicken chorioallantoic membrane resulted in a gross angiogenic response, and this effect was also inhibited by anti-CTGF antibodies. (iv) rCTGF injected with collagen gel into the backs of mice induced strong angiogenesis in vivo. These findings indicate that CTGF is a novel, potent angiogenesis factor which functions in multi-stages in this process.

These findings suggest that colonic luminal H(2)S/NaHS plays pronociceptive roles, and imply that the underlying mechanisms might involve sensitisation/activation of T-type channels probably in the primary afferents, aside from the issue of the selectivity of mibefradil.

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Recent studies have implicated a role for the trigeminal interpolaris/caudalis (Vi/Vc) transition zone in response to orofacial injury. Using combined neuronal tracing and Fos protein immunocytochemistry, we investigated functional connections between the Vi/Vc transition zone and rostral ventromedial medulla (RVM), a key structure in descending pain modulation. Rats were injected with a retrograde tracer, FluoroGold, into the RVM 7 days before injection of an inflammatory agent, complete Freund's adjuvant, into the masseter muscle and perfused at 2 hours postinflammation. A population of neurons in the ventral Vi/Vc overlapping with caudal ventrolateral medulla, and lamina V of the trigeminal subnucleus caudalis (Vc), exhibited FluoroGold/Fos double staining, suggesting the activation of the trigeminal-RVM pathway after inflammation. No double-labeled neurons were found in the dorsal Vi/Vc and laminae I-IV of Vc. Injection of an anterograde tracer, Phaseolus vulgaris leucoagglutinin, into the RVM resulted in labeling profiles overlapped with the region that showed FluoroGold/Fos double labeling, suggesting reciprocal connections between RVM and Vi/Vc. Lesions of Vc with a soma-selective neurotoxin, ibotenic acid, significantly reduced inflammation-induced Fos expression as well as the number of FluoroGold/Fos double-labeled neurons in the ventral Vi/Vc (P<0.05). Compared with control rats, lesions of the RVM (n=6) or Vi/Vc (n=6) with ibotenic acid led to the elimination or attenuation of masseter hyperalgesia/allodynia developed after masseter inflammation (P<0.05-0.01). The present study demonstrates reciprocal connections between the ventral Vi/Vc transition zone and RVM. The Vi/Vc-RVM pathway is activated after orofacial deep tissue injury and plays a critical role in facilitating orofacial hyperalgesia.

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Recent advances in the study of pain have revealed somatotopic- and modality-dependent processing and the integration of nociceptive signals in the brain and spinal cord. This review summarizes the uniqueness of the trigeminal sensory nucleus (TSN) in structure and function as it relates to orofacial pain control. The oral nociceptive signal is primarily processed in the rostral TSN above the obex, the nucleus principalis (Vp), and the subnuclei oralis (SpVo) and interpolaris (SpVi), while secondarily processed in the subnucleus caudalis (SpVc). In contrast, the facial nociceptive signal is primarily processed in the SpVc. The neurons projecting to the thalamus are localized mostly in the Vp, moderately in the SpVi, and modestly in the ventrolateral SpVo and the SpVc. Orofacial sensory inputs are modulated in many different ways: by interneurons in the TSN proper, through reciprocal connection between the TSN and rostral ventromedial medulla, and by the cerebral cortex. A wide variety of neuroactive substances, including substance P, gamma-aminobutyric acid, serotonin and nitric oxide (NO) could be involved in the modulatory functions of these curcuits. The earliest expression of NO synthase (NOS) in the developing rat brain is observed in a discrete neuronal population in the SpVo at embryonic day 15. NOS expression in the SpVc is late at postnatal day 10. The neurons receiving intraoral signals are intimately related with the sensorimotor reflexive function through the SpVo. In summary, a better understanding of the trigeminal sensory system--which differs from the spinal system--will help to find potential therapeutic targets and lend to developing new analgesics for orofacial-specific pain with high efficacy and fewer side effects.

Abstract. Glutamate (Glu) is the major excitatory neurotransmitter in the central nervous system. The role of peripheral Glu and Glu receptors (GluRs) in nociceptive transmission is, however, still unclear. In the present study, we examined Glu levels released in the subcutaneous perfusate of the rat hind instep using a microdialysis catheter and the thermal withdrawal latency using the Plantar Test following injection of drugs associated with GluRs with / without capsaicin into the hindpaw. The injection of capsaicin into the rat hind instep caused an increase of Glu level in the s.c. perfusate. Capsaicin also significantly decreased withdrawal latency to irradiation. These effects of capsaicin were inhibited by pretreatment with capsazepine, a transient receptor potential vanilloid receptor 1 (TRPV1) competitive antagonist. Capsaicin-induced Glu release was also suppressed by combination with each antagonist of ionotropic GluRs (iGluRs: NMDA / AMPA receptors) and group I metabotropic GluR (mGluR), but not group II and group III mGluRs. Furthermore, these GluRs antagonists showed remarkable inhibition against capsaicin-induced thermal hyperalgesia. These results suggest that Glu is released from the peripheral endings of small-diameter afferent fibers by noxious stimulation and then activates peripheral iGluRs and group I mGluR in development and/ or maintenance of nociception. Furthermore, the activation of peripheral NMDA / AMPA receptors and group I mGluR may be important in mechanisms whereby capsaicin evokes nociceptive responses.