This work was supported by the National Natural Science Foundation of China (Grant Nos. 39770848, 39830160), and a grant from NIH (DA 03983), USA. It is now well established that nerve growth factor (NGF) plays a key role in inammation-induced hyperalgesia. It was also reported that brain derived neurotrophic factor (BDNF), another member of neurotrophins, contributed to the pain pathway as a neurotransmitter in the CNS. The present work demonstrated a down-regulation of glial cell line-derived neurotrophic factor (GDNF) mRNA expression in dorsal spinal cord in complete Freund's adjuvant-induced unilateral arthritic rats serving as a chronic pain model. The fast occurring and long lasting down-regulations suggest that GDNF might contribute to pain pathway in a way different from neurotrophins and might play a role in the maintenance of chronic pain status. NeuroReport 11:737-741

Neurotrophic factors, such as nerve growth factor and brain-derived neurotrophic factor, are members of the structurally related neurotrophin family that play important roles in pain modulation. Although there are also indications for the involvement of glial cell line-derived neurotrophic factor (GDNF), it is unclear whether and how GDNF is involved in inflammatory pain. In the present study, we studied the expression pattern of GDNF in dorsal root ganglia (DRG) and spinal cord, using confocal microscopy. We demonstrate that GDNF is well associated with nonpeptidergic pain pathway and that GDNF could possibly be anterogradely transported from DRG neurons to superficial spinal cord dorsal horn. We also studied the dynamic changes of GDNF expression in rats during chronic inflammation using injection of complete Freund's adjuvant as a model of chronic pain. We found that GDNF was down-regulated in both dorsal root ganglia and spinal cords 2 weeks after arthritis induction. To assess the impact of this down-regulation on pain transmission, we used a function-blocking antibody against GDNF delivered intrathecally in the same chronic-pain animal models. Injection of this antibody to GDNF produced no immediate effect, but decreased the delayed, bilateral hyperalgesia induced from a unilateral injection of complete Freund's adjuvant. The effect of this antibody coincided with the downregulation of GDNF immunoreactivity in response to inflammation, suggesting that GDNF supports biochemical changes that contribute to hyperalgesia.

This work was designed to examine whether brain endomorphins (EM1 and EM2), the endogenous m-opioid ligands, are involved in electroacupuncture (EA)-induced analgesia in the mice. C57BL/6J mice were given EA for 30min and the effect of EA-induced analgesia was assessed by radiant heat tail-ick latency (TFL). Intracerebroventricular (i.c.v.) injection of m-opioid receptor antagonist D-Phe-Cys-Tyr-D-Tyr-Orn-Thr-Pen-Thr-NH2 (CTOP), or antiserum against EM1 or EM2 was performed to see whether EA analgesia could be blocked. The results showed that: (1) i.c.v. injection of CTOP at 25

Orphanin FQ (OFQ) and endomorphins (EM) are newly characterized members of opioid peptide family. OFQ has been shown to antagonize morphine analgesia at supraspinal level, whereas endomorphins are highly selective endogenous ligands for mu receptor, showing analgesic effect at both spinal and supraspinal level. OFQ and EM-2 (EM2) immunoreactivity (ir) was measured by radioimmunoassay in nociception-related brain areas of rats subjected to L5/L6 spinal nerve ligation, using shamoperated rats as control. Itwasfound that: (1) the content of EM2-ir of spinal nerve ligated rats showed a significant increase (778%) in periaqueductal gray (PAG), and a significant decrease (43%) in striatum, compared with the control group. (2) a significant increase of the content of OFQ-ir was found in amygdala (1841%) and PAG (1459%), respectively in spinal nerve ligated rats. High pressure liquid chromatography showed that the EM2-ir and OFQ-ir were both heterogeneous with the major part eluting at the position of EM2 and OFQ standard, respectively. These results suggest that spinal nerve ligation induces significant changes in the content of EM2-ir and OFQ-ir in some discrete brain areas, which may play a role in nociceptive modulation.

Interactions between selective opioid agonists acting at m- and d-opioid receptors were evaluated by co-administering a low-effective dose of the selective m-opioid receptor agonist ohmefentanyl (OMF) with sequentially increasing doses of the selective d-opioid receptor agonist [D-Pen2, D-Pen5] enkephalin (DPDPE). Microphysiometer was used to measure the extracellular acidification rate (ECAR) of living cells in real-time, which re-ected the functional activity after agonistreceptor binding. The synergy (i.e. a more than additive effect) was observed with combinations of these two opioid agonists on differentiated SH-SY5Y cells functionally expressing both m- and d-opioid receptors. The demonstration of the synergy suggests that the agonists of the subtypes of opioid receptors can interact at cellular level.

Recent studies have demonstrated the analgesic synergy between

The aim of the present study was to observe the effect of repeated subcutaneous (sc) injections of low doses of ketamine for the treatment of acute in

The aim of the present study was to characterize the effects of prolonged use of peptidem- and d-receptor agonists [D-Ala2, N-me-phe, Gly5-ol]-enkephalin (DAMGO) and [D-Pen2, D-Pen5]-enkephalin (DPDPE) and non-peptide agonists ohmefentanyl (OMF) and BW373U86 on the transcription of opioid receptors of cultured NG108-15 cell and SHSY5Y cells, respectively using the method of reverse transcription-polymerase chain reaction (RT-PCR). It was found that (1) The abundance of m- and d-receptor mRNA decreased significantly up to 48h after the administration of DAMGO and DPDPE, respectively; whereas the inhibitory effect of OMF and BW373U86 lasted only for 24h; (2) DAMGO and DPDPE produced a significant decrease of the mRNA coding for m-receptor andd-receptor at concentrations as low as 1028mol/L and 1026mol/L, respectively, whereas OMF and BW373U86 were effective at concentrations one order of magnitude higher, respectively. These results suggested that (1) Long-term administration of either peptide or non-peptide opioid agonist to cultured cell line produced a significant decrease of the gene expression of opioid receptor at transcription level. (2) The effect of peptide agonists was stronger and lasted longer than that of corresponding nonpeptide agonists.

The vanilloid receptor VR1 has attracted great interest as a sensory transducer for capsaicin, protons, and heat, and as a therapeutic target. Here we characterize two novel VR1 antagonists, KJM429 [N-(4-tert-butylbenzyl)-N -[4-(methylsulfonylamino) benzyl]thiourea] and JYL1421 [N-(4-tertbutylbenzyl)-N -[3-fluoro-4-(methylsulfonylamino)benzyl]-thiourea], with enhanced activity compared with capsazepine on rat VR1 expressed in Chinese hamster ovary (CHO) cells. JYL1421, the more potent of the two novel antagonists, inhibited [3H]resiniferatoxin binding to rVR1 with an affinity of 53.5

The vanilloid receptor VR1 is a polymodal nociceptor sensitive to capsaicin, protons, and heat. Because VR1 represents an attractive therapeutic target for conditions ranging from long-term pain to bladder hyperreflexia, we and other groups have sought to develop novel ligands with enhanced potencies and novel pharmacological properties. Here, we characterize two compounds, N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N -[4-(methylsulfonylamino)benzyl]thiourea (JYL827) and N-(4-tert-butylbenzyl)-N+-[3-methoxy-4-(methylsulfonylamino)benzyl]thiourea (JYL1511), that function as partial agonists for rat VR1 heterologously expressed in Chinese hamster ovary cells. Both compounds showed substantially enhanced potency, inhibiting [3H] resiniferatoxin binding with Ki values of 29.3