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.

In a rat phrenic nerve-hemidiaphragm preparation, calcitonin gene-related peptide (CGRP) increased the twitch contraction induced by nerve or transmural stimulation dose dependently. Either electrical or high K+ stimulation of the phrenic nerve caused release of a CGRP-like immunoreactive substance (CGRP-LIS) in a Ca2(+)-dependent manner. Electrical stimulation of the phrenic nerve also increased the cyclic AMP content in diaphragm. This increase was not observed in Ca2(+)-free medium and was blocked by antiserum against CGRP. These results indicate that excitation of the motor nerve causes release of CGRP-LIS at nerve terminals and that the released CGRP-LIS increases the cyclic AMP content of skeletal muscles and potentiates twitch contraction.

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.

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