Contusive spinal cord injury up regulates mu-opioid receptor (mor)gene expression in the brain and down regulates its expression in the spinal cord: possible implications in spinal cord injury research

Abstract

Traumatic spinal cord injury (SCI) is one of the dreaded neurological conditions and finding a cure for it has been a hot area of research. Naloxone - a mu-opiate receptor (mor) antagonist was considered for SCI treatment based on its positive effects under shock conditions. In contrary to animal studies based reports about the potential benefits of naloxone in treating SCI, a large scale clinical trial [National Acute Spinal Cord Injury Study II (NASCIS II)] conducted in USA failed to witness any effectiveness. The inconsistency noticed was intriguing. Therefore, the objective of the present study was to re-examine the role of naloxone in treating SCI using a highly standardised Multicenter Animal Spinal Cord Injury Study (MASCIS) animal model of contusive SCI. Results indicated that naloxone produced negligible and insignificant neuroprotection. In an attempt to understand the cause for the failure, it was found that mu-opioid receptor (mor) gene expression was upregulated in the brain but was down regulated in the spinal cord after contusive SCI. Given that the beneficial effects of naloxone are through its action on the mor, the results indicate that unlike the brain, spinal cord might not be bracing to utilise the opiate system in the repair process. This could possibly explain the failure of naloxone treatment in NASCIS II. To conclude, opiate antagonists like naloxone may be neuroprotective for treating traumatic brain injuries, but not for traumatic/contusive spinal cord injuries.

Altered transcription of glutamatergic and glycinergic receptors in spinal cord dorsal horn following spinal cord transection is minimally affected by passive exercise of the hindlimbs

“…Gene expression for the opioid receptors delta (DOR), kappa (KOR) and mu (MOR) was examined given their role in modulating nociception in the spinal cord (Przewlocki & Przewlocka, ) and that the MOR is up‐regulated in the brain and down‐regulated in the spinal cord following a contusive SCI (Michael et al ., ). In our study, no difference in gene expression was seen between the control and STx groups for any of the opioid receptors in laminae I‐III.…”

“…To date, studies have focused on laminae I-III gene expression in models of spinal cord contusion, incomplete spinal cord injury or peripheral nerve injury with little focus on a complete STx model (Novakovic et al, 1999;Tsuzuki et al, 2001;Michael et al, 2015), as these models induce a high level of neuropathic pain. However, the use of a complete STx model allows one to determine whether the maladaptive gene expression changes described in the previous injury models are present in the absence of spared descending supraspinal input and conscious awareness.…”

“…In these models, in which varying degrees of ascending and descending fibres remain intact (Novakovic et al, 1999;Woolf & Mannion, 1999;Tsuzuki et al, 2001;Michael et al, 2015), gene expression has been quantified by homogenizing the entire spinal cord or the dorsal horn, whereas the perception of pain is mediated in the superficial lamina (I to III) of the dorsal horn (Huang et al, 2016). As such, an examination of mRNA expression specific to the laminae associated with nociceptive signalling is an appropriate next step.…”

Spinal Cord Injury Induced Hyperalgesia is Associated with Increased Levels of Let-7 Family of MicroRNAs

“…One known effect of increased levels of the Let-7 family is repression of translation of the mu-opioid receptor, resulting in the loss of analgesic effect of opioids [20]. In animal models, SCI has been shown to reduce the expression levels of the mu opioid receptor (MOR) in the spinal cord [12,29]. The current data suggests that one mechanism behind the reduced number of MORs in the spinal cord after injury may be linked to upregulation of the Let-7 family of miRNAs.…”

“…Opioids are commonly employed for the treatment of SCI-related pain do not provide meaningful analgesia in all SCI patients [10,11]. Functional changes to the mu opioid receptor (MOR) have been observed following SCI, providing a potential explanation for why pain mitigation with opioids may be unsuccessful [12]. However, the mechanism behind these changes is not well understood MicroRNAs, small noncoding RNAs, are an emerging player in the field of pain research and have the potential to elucidate the chronic pain sequela associated with SCI at cellular level [13][14][15][16][17][18][19].…”