In the past Weiya Ma has collaborated on articles with Bruno St-Jacques and Zhiyong Wang. One of their most recent publications is Research reportChronic constriction injury of sciatic nerve induces the up-regulation of descending inhibitory noradrenergic innervation to the lumbar dorsal horn of mice. Which was published in journal Brain Research.

More information about Weiya Ma research including statistics on their citations can be found on their Copernicus Academic profile page.

Weiya Ma's Articles: (8)

Research reportChronic constriction injury of sciatic nerve induces the up-regulation of descending inhibitory noradrenergic innervation to the lumbar dorsal horn of mice

AbstractPeripheral nerve injury in rodents results in hypersensitivity to mechanical and thermal stimuli accompanied by reduced antinociceptive efficacy of opioids and, in some models, sensitivity to sympathetic blockade. α2-Adrenergic receptor agonists increase in potency and efficacy after nerve injury in rodents and effectively relieve neuropathic pain in humans who do not get pain relief from opioids. However, the underlying mechanisms are unclear. It has been well known that the major noradrenergic innervation of the spinal dorsal horn originates from the locus coeruleus nucleus (LC) in the brainstem. Therefore, the aim of this study is to examine whether peripheral nerve injury that causes neuropathic pain modulates the noradrenergic innervation to the lumbar dorsal horn, in order to determine the possible anatomical substrates underlying increased potency and efficacy of noradrenergic receptor agonists in alleviating neuropathic pain. At 2 weeks after chronic constriction injury (CCI) of the sciatic nerve, a remarkable increase in tyrosine-hydroxylase (TH) and dopamine β-hydroxylase (DβH) immunoreactive (IR) axonal terminals was observed in the ipsilateral L4–L6 dorsal horn. Consistently, greater numbers of both TH- and DβH-IR neurons were detected in the ipsilateral LC. Interestingly, in the lower lumbar and upper sacral spinal dorsal horn, numerous TH-IR neurons were observed in the superficial dorsal horn (primarily lamina I). CCI of the sciatic nerve did not change the number of these TH-IR cells. These findings suggest that augmented descending inhibitory noradrenergic innervation to the dorsal horn could be one of the mechanisms underlying the increased effectiveness in the anti-allodynic effect elicited by α2-adrenergic receptor agonists.

Research reportIntrathecal injection of cAMP response element binding protein (CREB) antisense oligonucleotide attenuates tactile allodynia caused by partial sciatic nerve ligation

AbstractThe transcription factor cAMP responsive element binding protein (CREB) is important in regulating immediate-early genes and some late-effector genes involved in neuroplasticity in response to peripheral injury and stressful insults. Partial nerve injury elicited neuropathic pain is accompanied by increased phosphorylation of CREB in the ipsilateral spinal cord dorsal horn (Ma and Quirion, Pain 93 (2001) 295; Miletic et al., Pain 99 (2002) 493). The aim of this study is to determine whether increased phosphorylation of CREB in the dorsal horn contributes to the pathogenesis of neuropathic pain. Three weeks following partial sciatic nerve ligation (PSNL), daily intrathecal injection of antisense CREB oligodeoxynucleotide (ODN, 20 μg/day) for 5 days significantly attenuated tactile allodynia. The attenuation lasted for more than 4 days. Total CREB and phosphorylated CREB in both ipsilateral and contralateral dorsal horn neurons were dramatically reduced in antisense ODN injected PSNL rats 1 week after injection. The extent of reduction of total CREB and phosphorylated CREB containing cells in the dorsal horn ipsilateral to injury was greater than in the contralateral dorsal horn. These data suggest that phosphorylation of CREB is an important contributing event in the central plasticity of nerve injury and in the pathogenesis of neuropathic pain.

Research reportIncreased activation of nuclear factor kappa B in rat lumbar dorsal root ganglion neurons following partial sciatic nerve injuries

AbstractNuclear factor kappa B (NFκB) is a transcription factor which can be activated by some neurotrophic factors and cytokines, and then translocated into the nucleus. We examined NFκB immunoreactivity (IR) in L4 and L5 dorsal root ganglion (DRG) cells of normal rats, and 2 weeks after complete sciatic nerve transection (CSNT), partial sciatic nerve ligation (PSNL) and chronic constriction injury (CCI). In the normal DRG, 45% of the neurons were NFκB-IR (IR in cytoplasm only or in both cytoplasm and nucleus). Only 18% were activated NFκB-IR cells (IR in both cytoplasm and nucleus). Two weeks after CSNT, PSNL and CCI, there was no significant difference in the percentages of NFκB-IR neurons between the ipsilateral and contralateral DRG. However, the percentages of the activated NFκB-IR neurons in the ipsilateral DRG of PSNL (30%) and CCI (33%) rats, but not in CSNT (24%) rats, were significantly increased, compared with the contralateral DRG. Ultrastructurally, NFκB-IR was localized to the endoplasmic reticulum and Golgi apparatus. In activated cells, IR was also observed in the nuclei. Two weeks after CCI, NFκB-IR was stronger in the axons and Schwann cells in the proximal stump of the injured sciatic nerves than in uninjured contralateral nerves. In some Schwann cells surrounding unmyelinated fibers, the nuclei were also NFκB-IR, suggesting that these cells were activated by CCI. NFκB activation increased in DRG neurons and Schwann cells 2 weeks following partial sciatic injuries, possibly in response to cytokines and neurotrophins produced by endoneurial cells in the partially injured nerve during Wallerian degeneration.

Regular articleFour PGE2 EP receptors are up-regulated in injured nerve following partial sciatic nerve ligation

AbstractWe previously reported that cyclooxygenase 2 (COX2) is up-regulated in macrophages in injured nerve of rats with partial sciatic nerve ligation (PSNL) and that local injection of the COX inhibitor ketorolac reversed tactile allodynia (Eur. J. Neurosci. 15: 1037–1047, 2002). These findings suggest that prostaglandins (PGs) are overproduced in injured nerve and are involved in the pathogenesis of neuropathic pain. In this study, we examined whether overproduced PGs alter the expression of PGE2 receptors, EP1–EP4, in injured nerve of PSNL rats. We found that cell profiles immunoreactive (IR) for four EP receptors, EP1, EP2, EP3, and EP4, are dramatically increased in injured nerve 2 and 4 weeks after PSNL. EP4-IR cells were the most abundant among these receptor-expressing cells. Immunoreactivities of all four EP receptors were localized to the cell nucleus. These EP-IR cells were never found in uninjured nerve. More than 80% EP1- and about 30% EP4-IR cells were identified as infiltrating macrophages since they coexpressed ED1. Only 3% EP2- and 6% EP3-IR cells coexpressed ED1. These findings suggest that majority of EP2-, EP3-, and EP4-IR cells are other types of inflammatory cells than macrophages. About 48% of macrophages expressed EP1 and 45% expressed EP4. Only 3 and 6% of macrophages, respectively, expressed EP2 and EP3. Perineural injection of ketorolac reversed tactile allodynia and suppressed the up-regulation of EP1 and EP4, but not the recruitment of ED1-IR marcrophages, in injured nerve. Our data suggest that following PSNL, PGE2 is one of the possible PGs overproduced in injured nerve and PG overproduction is involved in the up-regulation of EP receptors in injured nerve.

Regular ArticlePeripheral prostaglandin E2 prolongs the sensitization of nociceptive dorsal root ganglion neurons possibly by facilitating the synthesis and anterograde axonal trafficking of EP4 receptors

Highlights•Intraplantar injection of long-lasting dmPGE2 dose- and time-dependently elicited primary pain.•Pre-injection of dmPGE2 prolonged pain evoked by a subsequent dmPGE2 injection.•Duration of pain was progressively prolonged following multiple sequential dmPGE2 injections.•Inhibiting EP1, EP4, cAMP, PKA, PKC, PKCε, PLC or IL-6 prevented dmPGE2-prolonged pain.•Injection of dmPGE2 or carrageenan increased EP4 levels in DRG and nerves.

Increased phosphorylation of cyclic AMP response element-binding protein (CREB) in the superficial dorsal horn neurons following partial sciatic nerve ligation

AbstractPartial sciatic nerve injury causes neuropathic pain associated with behavioral changes such as spontaneous pain, hyperalgesia and allodynia. Both central and peripheral sensitization of pain pathways are likely to be involved in these alterations. Nerve injury induced plastic changes in the dorsal horn, where the second relay nociceptive neurons are located, may contribute to the central sensitization process. It is thus important to establish the intracellular events through which a partial nerve injury can induce plasticity leading to neuropathic pain. In this study, we investigated whether partial sciatic nerve ligation (PSNL), a well-characterized neuropathic pain model, is able to induce the phosphorylation of a transcription factor, known as the cyclic AMP response element-binding protein (CREB) which is believed to be involved in the transcriptional regulation of many genes. Using immunocytochemistry, we found that 3 weeks following PSNL, the number of phosphorylated (p) CREB-IR cells was significantly increased in the injured side dorsal horn of rats, particularly in the superficial laminae. Interestingly, the majority of pCREB-IR cells expressed protein kinase Cγ, an enzyme shown to be involved in the development of neuropathic pain in PSNL model. Taken together, these results suggest that increased CREB phosphorylation induced by PSNL may be one of the key molecular events leading to synaptic alterations and persistent pain in the PSNL model of neuropathic pain.

Calcitonin gene-related peptide as a regulator of neuronal CaMKII–CREB, microglial p38–NFκB and astroglial ERK–Stat1/3 cascades mediating the development of tolerance to morphine-induced analgesia

AbstractTolerance to morphine-induced analgesia is an intractable phenomenon, often hindering its prolonged applications in the clinics. The enhanced pronociceptive actions of spinal pain-related molecules such as calcitonin gene-related peptide (CGRP) may underlie this phenomenon and could be a promising target for intervention. We demonstrate here how CGRP regulates the development of morphine analgesic tolerance at the spinal level. A 7-day treatment with morphine led to tolerance to its analgesic effects and enhanced expression of CGRP and its receptor subunits calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein 1 (RAMP1). Activation of several cell-type-specific kinase transcription factor cascades is required to mediate this tolerance, including calcium/calmodulin-dependent protein kinase II (CaMKII) and cAMP response element-binding protein (CREB) in neurons, p38 and nuclear factor kappa B (NFκB) in microglia and extracellular signal-regulated protein kinase (ERK) and signal transducer and activator of transcription 1 and 3 (Stat1/3) in astrocytes, because inhibitors of CaMKII, p38 and ERK pathways correspondingly reduced the increases in phosphorylated CREB, acetylated-NFκB and phosphorylated Stat1/3 levels and attenuated the development of tolerance. Interestingly, these cascades were linked to the regulation of glutamatergic N-methyl-d-aspartate (NMDA) receptor expression. Chronic morphine-induced behavioural responses and biochemical events were all subjugated to modulation by disrupting CGRP receptor signaling. Together, these data suggest that CGRP contributes to the development of tolerance to morphine-induced analgesia by regulating the activation of the neuronal CaMKII–CREB, microglial p38–NFκB and astroglial ERK–Stat1/3 cascades. Targeting CGRP-associated signaling molecules may prolong or restore morphine’s analgesic properties upon a chronic exposure.

Prostaglandin E2/EP4 signalling facilitates EP4 receptor externalization in primary sensory neurons in vitro and in vivo

AbstractInflammatory pain severely affects the quality of life of millions of individuals worldwide. Prostaglandin E2 (PGE2), a pain mediator enriched in inflamed tissues, plays a pivotal role in nociceptor sensitization and in the genesis of inflammatory pain. Its EP4 receptor mainly mediates its role in inflammatory pain. However, the underlying mechanisms are poorly understood. Here we found that PGE2/EP4 signalling-induced EP4 externalization in dorsal root ganglion (DRG) neurons contributes to nociceptor sensitization and inflammatory pain. In cultured DRG neurons, PGE2 and the EP4 agonist concentration- and time-dependently stimulated EP4 externalization. The inhibitors of anterograde secretory pathway, protein synthesis, or recycling pathway suppressed PGE2-induced EP4 externalization, suggesting that EP4 retained in Golgi apparatus and in recycling endosomes, as well as newly synthesized, are mobilized in this event. Interestingly, the intracellular cAMP levels of cultured DRG explants following 2 sequential treatments with the EP4 agonist were significantly higher than a single treatment, suggesting that the first treatment of agonist likely induces EP4 export to sensitize DRG neurons. Intraplantar injection of complete Freud’s adjuvant increases both total and cell-surface EP4 levels of L4-6 DRG neurons, an event suppressed by a cyclooxygenase-2 inhibitor or a selective EP4 antagonist, suggesting that PGE2/EP4 signalling in inflamed paw contributes to EP4 synthesis and export in DRG neurons, thus sensitizing nociceptors during inflammation. We conclude that PGE2/EP4 signalling-induced EP4 externalization in DRG neuron is a novel mechanism underlying nociceptor sensitization and inflammatory pain. Blocking EP4 externalization could open a novel therapeutic avenue to treat inflammatory pain.

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