Activation of p38 mitogen-activated protein kinase in spinal microglia mediates morphine antinociceptive tolerance

Bancroft

2017

Journal of Neurotrauma

Opioids are frequently used for the treatment of pain following spinal cord injury (SCI). Unfortunately, we have shown that morphine administered in the acute phase of SCI results in significant, adverse secondary consequences including compromised locomotor and sensory recovery. Similarly, we showed that selective activation of the j-opioid receptor (KOR), even at a dose 32-fold lower than morphine, is sufficient to attenuate recovery of locomotor function. In the current study, we tested whether activation of the KOR is necessary to produce morphine's adverse effects using norBinaltorphimine (norBNI), a selective KOR antagonist. Rats received a moderate spinal contusion (T12) and 24 h later, baseline locomotor function and nociceptive reactivity were assessed. Rats were then administered norBNI (0, 0.02, 0.08, or 0.32 lmol) followed by morphine (0 or 0.32 lmol). Nociception was reassessed 30 min after drug treatment, and recovery was evaluated for 21 days. The effects of norBNI on morphine-induced attenuation of recovery were dose dependent. At higher doses, norBNI blocked the adverse effects of morphine on locomotor recovery, but analgesia was also significantly decreased. Conversely, at low doses, analgesia was maintained, but the adverse effects on recovery persisted. A moderate dose of norBNI, however, adequately protected against morphine's adverse effects without eliminating its analgesic efficacy. This suggests that activation of the KOR system plays a significant role in the morphineinduced attenuation of recovery. Our research suggests that morphine, and other opioid analgesics, may be contraindicated for the SCI population. Blocking KOR activity may be a viable strategy for improving the safety of clinical opioid use.

Section: Resultsmentioning

confidence: 69%

Nor-Binaltorphimine Blocks the Adverse Effects of Morphine after Spinal Cord Injury

Bancroft

2017

Journal of Neurotrauma

Journal of Neuroscience

“…3H). Given that chronic morphine can activate microglial p38 MAPK in the spinal cord (Cui et al, 2006), our data suggest that BBG treatment attenuated morphine analgesic tolerance at least partly by inhibiting the activation of spinal microglia.…”

Section: Upregulation Of Spinal Microglial Expression and P2x 7 Rs Inmentioning

confidence: 75%

“…It has been reported that p38 MAPK, a transducer of various extracellular stimuli, regulates the release of inflammatory factors (Saklatvala, 2004) and is involved in the development of morphine analgesic tolerance associated with microglia (Cui et al, 2006(Cui et al, , 2008. Therefore, we examined the effect of p38 MAPK on P2X 7 R-mediated morphine tolerance.…”

Section: Discussionmentioning

confidence: 98%

Involvement of Spinal Microglial P2X7 Receptor in Generation of Tolerance to Morphine Analgesia in Rats

Zhou

Chen²,

Zhang³

2010

102

Morphine loses analgesic potency after repeated administration. The underlying mechanism is not fully understood. Glia are thought to be involved in morphine tolerance, and P2X 7 purinergic receptor (P2X 7 R) has been implicated in neuron-glia communication and chronic pain. The present study demonstrated that P2X 7 R immunoreactivity was colocalized with the microglial marker OX42, but not the astrocytic marker GFAP, in the spinal cord. The protein level of spinal P2X 7 R was upregulated after chronic exposure to morphine. Intrathecal administration of Brilliant Blue G (BBG), a selective P2X 7 R inhibitor, significantly attenuated the loss of morphine analgesic potency, P2X 7 R upregulation, and microglial activation. Furthermore, RNA interference targeting the spinal P2X 7 R exhibited a similar tolerance-attenuating effect. Once morphine analgesic tolerance is established, it was no longer affected by intrathecal BBG. Together, our results suggest that spinal P2X 7 R is involved in the induction but not maintenance of morphine tolerance.

Brain, Behavior, and Immunity

“…In last several years, different laboratories have shown that p38 is activated in spinal microglia under different pain conditions. Importantly, p38 activation also contributes to the development of pain hypersensitivity (Ji et al, 2002b;Kim et al, 2002;Jin et al, 2003;Svensson et al, 2003, Tsuda et al, 2004Cui et al, 2006;Piao et al, 2006). Therefore, p38 activation (phosphorylation) could serve as a marker for microglial activation in the spinal cord under different pain conditions.…”

Section: P38 Activation In Spinal Microglia and Neuropathic Painmentioning

confidence: 99%

Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine

Zhuang

Kawasaki

Tan

et al. 2007

323

317

Accumulating evidence suggests that microglial cells in the spinal cord play an important role in the development of neuropathic pain. However, it remains largely unknown how glia interact with neurons in the spinal cord after peripheral nerve injury. Recent studies suggest that the chemokine fractalkine may mediate neural/microglial interaction via its sole receptor CX3CR1. We have examined how fractalkine activates microglia in a neuropathic pain condition produced by spinal nerve ligation (SNL). SNL induced an upregulation of CX3CR1 in spinal microglia that began on day 1, peaked on day 3, and maintained on day 10. Intrathecal injection of a neutralizing antibody against CX3CR1 suppressed not only mechanical allodynia but also the activation of p38 MAPK in spinal microglia following SNL. Conversely, intrathecal infusion of fractalkine produced a marked p38 activation and mechanical allodynia. SNL also induced a dramatic reduction of the membranebound fractalkine in the dorsal root ganglion, suggesting a cleavage and release of this chemokine after nerve injury. Finally, application of fractalkine to spinal slices did not produce acute facilitation of excitatory synaptic transmission in dorsal horn neurons, arguing against a direct action of fractalkine on spinal neurons. Collectively, our data suggest that (a) fractalkine cleavage (release) after nerve injury may play an important role in neural-glial interaction, and (b) microglial CX3CR1/ p38 MAPK pathway is critical for the development of neuropathic pain.