No abstract

At the spinal level, nociceptin/orphanin FQ (Noc/OFQ) produces pronociceptive and allodynic effects at low doses (picogram range), while causing antinociceptive effects at high doses (microgram range). The discrepancy of pain modulation by Noc/OFQ at low and high doses raised a question whether Noc/OFQ exerted actions through the same Noc/OFQ receptor. In the present study, we examined the involvement of the Noc/OFQ receptor in pain responses with the novel nonpeptide antagonist N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride (JTC-801). Allodynia and hyperalgesia evoked by intrathecal administration of Noc/OFQ (50 pg/mouse) were dose dependently blocked by simultaneous administration of JTC-801 with IC 50 values of 32.2 and 363 pg, respectively. JTC-801 did not induce allodynia by itself. Subcutaneous injection of formalin into a hindpaw evoked biphasic pain behaviors such as flinching and biting in mice. Noc/OFQ at 10 pg increased the second-phase pain behaviors evoked by 1% formalin, whereas it strongly inhibited both the first-phase and second-phase pain evoked by 2% formalin at 1 g. Although the pronociceptive effect by 10 pg of Noc/OFQ was dose dependently blocked by JTC-801 with an IC 50 value of 4.58 pg, the antinociceptive effects by 1 g of Noc/OFQ were not antagonized by JTC-801. Furthermore, both phases of 2% formalin-induced pain behaviors were relieved by JTC-801. These results demonstrate that pronociceptive responses induced by a low dose of Noc/OFQ may be mediated through the Noc/OFQ receptor in the spinal cord and that JTC-801 can be a useful antagonist to examine the involvement of endogenous Noc/OFQ and mediation of the Noc/OFQ receptor under physiological and pathophysiological conditions including pain.

Prostaglandin F 2a (PGF 2a ) binds to its receptor (FP) to increase the intracellular-free calcium concentration ([Ca

No abstract

The restoration of function to injured peripheral nerves separated by a gap requires regeneration across it and reinnervation to target organs. To elucidate these processes, we have established an in vivo monitoring system of nerve regeneration in thy1-yellow fluorescent protein transgenic mice expressing a fluorescent protein in their nervous system. Here we demonstrated that motor and sensory nerves were regenerated in a coordinated fashion across the gap and that the functional recovery of the response to mechanical stimuli correlated well with sensory innervation to the foot. Among the mitogen-activated protein kinase inhibitors examined, only the c-Jun N-terminal kinase (JNK) inhibitors delayed functional recovery. Although it did not affect the reinnervation of the muscle, the JNK inhibitor delayed sensory nerve innervation to the skin for over 8 weeks and increased the expression of activatng transcription factor 3 (ATF3), a neuronal injury marker, in the dorsal root ganglion over the same time period. Antibodies against nerve growth factor, glia-derived neurotrophic factor, and brain-derived neurotrophic factor applied to the transection site delayed the functional recovery in this order of potency. These neurotrophic factors enhanced neurite outgrowth from cultured dorsal root ganglion neurons, and the JNK inhibitor reversed their stimulatory effects. These results suggest that JNK played roles in nerve regeneration at both early and late phases. Taken together, the present study demonstrated that neurotrophic factors released from the distal nerve may accelerate motor and sensory nerve regeneration across the gap in a coordinated fashion and reinnervation of the target organs independently. The model characterized here has the advantage of in vivo monitoring of the evaluation of morphological and functional recovery in the same mice for a long period of time.