Epiregulin (EREG) associated with disc herniation induces spontaneous activity in the pain pathways.

Low back pain and sciatica after disc herniation may be caused by mechanical compression of the nerve roots, but also by the release of pro-inflammatory agents and growth factors from the nucleus pulposus (NP) of the herniated disc. In the present study the functional changes in nociceptive signaling due to disc herniation were investigated. NP tissue was harvested from tail vertebrae and incubated in cell medium to examine if NP cells were able to secrete epiregulin (EREG), a member of the epidermal growth factor (EGF) family. Extracellular single-cell recordings in the spinal dorsal horn (DH) were performed to investigate the effect of EREG on neuronal excitability. The expression of EREG and its receptors were examined by qPCR in NP tissue, DH of the spinal cord, and the dorsal root ganglions (DRG). The present data demonstrated that EREG may be released after disc herniation from NP tissue. Directly administration of EREG onto the spinal dorsal nerve roots induced a decrease in responsiveness to electrical stimuli, but a pronounced increase in spontaneous activity in nociceptive neurons. A significant up-regulation of the gene encoding EREG was observed in the DH, when NP tissue was exposed to the spinal dorsal nerve roots. The EREG receptors EGFR and HER4 were up-regulated in NP tissue and DH tissue, whereas HER3 was up-regulated in DRGs. Taken together, our findings suggest that EREG signaling through its receptors may induce sensory abnormalities and pain hypersensitivity following a disc herniation

Prenatal exposure to methadone or buprenorphine impairs cognitive performance in young adult rats

Background Concerns have been raised about the use of opioid maintenance treatment (OMT) during pregnancy and negative effects for the offspring. While neonatal outcomes and short-term effects are relatively well described, studies examining long-term effects in adolescents and adults are absent. The aim of the present study was to examine effects on learning and memory in young adult rats prenatally exposed to methadone or buprenorphine. Methods Female rats were implanted with a 28-day osmotic minipump delivering methadone (10 mg/kg/day), buprenorphine (1 mg/kg/day) or vehicle 5 days prior to mating. To examine possible effects on cognitive functioning, young adult offspring were included in three different behavioral tests that examine recognition memory, nonspatial, and spatial learning and memory. In addition, offspring growth and maternal behavior after birh were investigated. Results Prenatal exposure to methadone or buprenorphine caused impaired recognition memory and nonspatial reference learning and memory in young adult rats compared with the vehicle-treated group. Methadone-exposed offspring, but not the buprenorphine-exposed, also showed reduced long-term spatial memory. We did not observe any changes in maternal behavior or offspring growth after prenatal exposure to methadone or buprenorphine, suggesting that the impaired cognitive functioning is due to the opioid exposure rather than reduced maternal caregiving. Conclusion The present findings of long-term cognitive impairments in methadone- and buprenorphine-exposed offspring points to a negative impact of OMT on neurobiological development

Epiregulin is released from intervertebral disks and induces spontaneous activity in pain pathways

Abstract. Introduction:. Lumbar radicular pain after disk herniation is associated with local release of many inflammatory molecules from nucleus pulposus (NP) cells leaking out of the intervertebral disk. Here, we have used a rat model to investigate the role of epiregulin (EREG), a member of the epidermal growth factor (EGF) family, in this process. Methods:. A protein immunoassay was chosen to confirm the release of EREG from the NP tissue. Single unit recordings were used to demonstrate the effect of recombinant EREG applied onto the dorsal nerve roots in vivo. Intracellular responses induced by recombinant EREG were studied in cultured dorsal root ganglion (DRG) cells by phosphoprotein assay. Changes in EGF receptor expression induced by NP in the DRG were examined by quantitative polymerase chain reaction. Results:. The protein immunoassay showed that EREG was released from the NP tissue. Moreover, application of EREG onto the spinal dorsal nerve roots induced a decrease in the evoked responses, but an increase in spontaneous activity in the dorsal horn neurons. Interestingly, the EREG activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in the DRG, a pathway previously linked to cellular growth, proliferation, and tissue regeneration. An NP-induced upregulation of the EGF receptor HER3 in the DRG was also revealed. Conclusion:. Taken together, the present observations indicate that EREG may induce changes in the DRG and spontaneous activity in the pain pathways. We suggest that EREG signaling may be involved in the pathophysiological process leading to sensory deficits and neuropathic pain in patients after disk herniation

Prenatal exposure to methadone or buprenorphine alters µ-opioid receptor binding and downstream signaling in the rat brain

There is a growing concern related to the use of opioid maintenance treatment during pregnancy. Studies in both humans and animals have reported reduced cognitive functioning in offspring prenatally exposed to methadone or buprenorphine; however, little is known about the neurobiological mechanisms underlying these impairments. To reveal possible neurobiological effects of such in utero exposure, we examined brain tissue from methadone‐ and buprenorphine‐exposed rat offspring previously shown to display impaired learning and memory. We studied µ‐opioid receptor (MOR) and N‐methyl‐D‐aspartate receptor (NMDAR) binding in the rat offspring cerebrum during development and in the hippocampus at young adulthood. Moreover, we examined activation of the Ca2+/calmodulin‐dependent protein kinase II (CaMKII) and the extracellular signal‐regulated kinase (ERK), which are central in the downstream signaling of these receptors. The methadone‐ and buprenorphine‐exposed rat pups displayed reduced MOR binding up to two weeks after birth, whereas the NMDAR binding was unaffected. Prenatal exposure to methadone or buprenorphine also resulted in decreased activation of CaMKII and/or ERK during development, while young adult offspring displayed increased hippocampal ERK activation. In conclusion, our findings suggest that prenatal exposure to exogenous opioids, such as methadone or buprenorphine, may disturb the endogenous opioid system during development, with long‐term effects on proteins important for cognitive functioning