Inhibition of SNL-induced upregulation of CGRP and NPY in the spinal cord and dorsal root ganglia by the 5-HT(2A) receptor antagonist ketanserin in rats.

Our previous study has demonstrated that topical and systemic administration of the 5-HT(2A) receptor antagonist ketanserin attenuates neuropathic pain. To explore the mechanisms involved, we examined whether ketanserin reversed the plasticity changes associated with calcitonin gene-related peptides (CGRP) and neuropeptide Y (NPY) which may reflect distinct mechanisms: involvement and compensatory protection. Behavioral responses to thermal and tactile stimuli after spinal nerve ligation (SNL) at L5 demonstrated neuropathic pain and its attenuation in the vehicle- and ketanserin-treated groups, respectively. SNL surgery induced an increase in CGRP and NPY immunoreactivity (IR) in laminae I-II of the spinal cord. L5 SNL produced an expression of NPY-IR in large, medium and small diameter neurons in dorsal root ganglion (DRG) only at L5, but not adjacent L4 and L6. Daily injection of ketanserin (0.3 mg/kg, s.c.) for two weeks suppressed the increase in CGRP-IR and NPY-IR in the spinal cord or DRG. The present study demonstrated that: (1) the expression of CGRP was enhanced in the spinal dorsal horn and NPY was expressed in the DRG containing injured neurons, but not in the adjacent DRG containing intact neurons, following L5 SNL; (2) the maladaptive changes in CGRP and NPY expression in the spinal cord and DRG mediated the bioactivity of 5-HT/5-HT(2A) receptors in neuropathic pain and (3) the blockade of 5-HT(2A) receptors by ketanserin reversed the evoked upregulation of both CGRP and NPY in the spinal cord and DRG contributing to the inhibition of neuropathic pain.

Wang D ，Chen T ，Gao Y ，Quirion R ，Hong Y ... -  《-》

Topical and systemic administrations of ketanserin attenuate hypersensitivity and expression of CGRP in rats with spinal nerve ligation.

The aim of this study was to examine the involvement of 5-HT and 5-HT(2A) receptors in neuropathic pain and their possible cellular mechanism. To evaluate a potential therapy the 5-HT(2A) receptor antagonist ketanserin was administered topically or subcutaneously in rats with L5 nerve ligation. Unilateral spinal nerve ligation induced hypersensitivity to thermal and mechanical stimuli in the ipsilateral hindpaw and an increase in calcitonin gene-related peptide (CGRP) immunoreactivity (CGRP-IR) in small and medium diameter neurons in dorsal root ganglia (DRG) at L4 and L6, but not at L5. Topical application of ketanserin (3%) delivered in a mixture of gelatin, glycerol and kaolin onto skin over the hindpaw produced significant elevation of nociceptive threshold in the paw. Daily injection of ketanserin inhibited the thermal hyperalgesia in a dose dependent manner (0.1 and 0.3mg/kg, s.c.). The inhibition occurred at 1-3 days after the injection started and persisted for at least 2 weeks without decline. Injection of ketanserin (0.3mg/kg) also suppressed tactile allodynia. Moreover, ketanserin (0.3mg/kg) reversed the increase in CGRP-IR expression in L4 and L6 DRG neurons. These results support the hypothesis that adaptive change in CGRP expression that occurred in the DRG adjacent to the DRG containing injured neurons underlies the nerve ligation-induced hypersensitivity. This study suggests that 5-HT and 5-HT(2A) receptors contribute to the maintenance of neuropathic pain by up-regulating the expression of CGRP-IR, and that topical and systemic administrations of ketanserin are promising therapies for relieving neuropathic pain without tolerance.

Wang D ，Gao Y ，Ji H ，Hong Y ... -  《-》

Antagonism of 5-HT(2A) receptors inhibits the expression of pronociceptive mediator and enhances endogenous opioid mechanism in carrageenan-induced inflammation in rats.

We have recently reported that treatment with the 5-HT(2A) receptor antagonist ketanserin in the inflamed paw raises the nociceptive threshold above normal level (hypoalgesia) and this response is naloxone-reversible. The present study aimed to investigate neurochemical changes at the site of inflammation and in dorsal root ganglia (DRG) and the spinal cord following the blockade of 5-HT(2A) receptors. Intraplantar injection of ketanserin (20 μg) inhibited carrageenan-induced increase in CGRP immunoreactivity-positive neurons in DRG. On the other hand, administration of ketanserin (20 μg) and 5-HT (10 μg), but not vehicle, enhanced and inhibited recruitment of β-endorphin-expressing immune cells, respectively, in subcutaneous loci of inflamed hindpaw. Moreover, the treatment with ketanserin increased the number of endomorphine-containing cells in the inflamed paw and μ-opioid receptor-expressing neurons in DRG at L4-5 but reduced the expression of endomorphine in superficial layers of the lumbar spinal cord. The present study provided evidence at the cellular level showing that the blockade of 5-HT(2A) receptors inhibited inflammation-associated increase in pronociceptive mediator, and that the pronociceptive property of 5-HT is mediated by the suppression of inflammation-activated opioid mechanism. Therefore, targeting the 5-HT(2A) receptors in the site of inflammation may be a promising approach to inhibit inflammatory pain.

Huang J ，Fan Y ，Jia Y ，Hong Y ... -  《-》

Calcitonin gene-related peptide dynamics in rat dorsal root ganglia and spinal cord following different sciatic nerve injuries.

Zheng LF ，Wang R ，Xu YZ ，Yi XN ，Zhang JW ，Zeng ZC ... -  《BRAIN RESEARCH》

Pre-emptive intrathecal quinidine alleviates spinal nerve ligation-induced peripheral neuropathic pain.

Quinidine, a class I anti-arrhythmic agent, is a sodium channel blocker that is more potent than lidocaine and mexiletine. This study tested pre-emptive intrathecal quinidine to attenuate neuropathic pain induced by lumbar spinal nerve ligation (SNL). Ninety-six adult male Sprague-Dawley rats were grouped equally (n=24 per group) as follows: group S (sham), removal of transverse process only; group L, SNL; group Q₃₅, SNL pretreated with intrathecal quinidine 35 mM (50 µl); group Q₇₀, SNL pretreated with intrathecal quinidine 70 mM (50 µl). Neuropathic pain was measured by thermal hyperalgesia and mechanical allodynia. Other measurements included dys-regulation of sodium channel Nav₁.₃ in dorsal root ganglion (DRG) and spinal microglia activation in spinal dorsal horn. Spinal nerve ligation induced abnormal mechanical allodynia and thermal hyperalgesia, up-regulated Nav₁.₃ in DRG, and activated microglia in spinal cord. Group Q₇₀ showed attenuated thermal hyperalgesia (P<0.001) and mechanical allodynia (P<0.05) on postoperative day 5 (POD₅) but not on POD₇, reversed up-regulated expression of Nav₁.₃ on POD₃ and POD₇ in DRG and significantly attenuated microglia activation on POD₇ (P=0.032) in spinal cord. Pretreatment with intrathecal quinidine 70 mM before SNL attenuates nerve ligation-induced neuropathic pain. The duration of the effect is 5 days.

Cheng KI ，Wang HC ，Lai CS ，Tsai HP ，Kwan AL ，Ho ST ，Wang JJ ，Chang LL ... -  《-》