Instituut voor Neuropathische Pijn

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Opioids activate Glia: counterproductive in neuropathic pain...

Opioids can cause chronic pain, especially neuropathic pain, were glia and asterocytes are happy to become over activated. After chronic opiate exposure, this excitatory effect emerges contributing to analgesic tolerance and opioid-induced hyperalgesia, and the glia are key in this negative pain cascade.

Opioids in chronic pain are limited in its use due to side effects, tolerance and hyperalgesia.

Morphine. a classical opioid, increased microglial migration via a novel interaction between mu-opioid and P2X(4) receptors. This activation is dependent upon the PI3K/Akt pathway.

Due to the activation by morphine, primary microglial cells migrate and this opioid-dependent migration effect was inhibited by naloxone and confirmed to be mu-opioid receptor-dependent through the use of selective agonists and antagonists.

The P2X(4) receptor expression could significantly be increased after 6, 12, 24, and 48 h of morphine stimulation.

Based on in vitro studies two phases of morphine effects on microglia seem to exist:

the initial phase takes place in minutes, involves PI3K/Akt pathway activation and leads to acutely enhanced migration.
a longer-term phase occurs on the order of hours and involves increased expression of Iba1 and P2X(4) receptor protein

Microglial migration is an attractive target for the prevention or attenuation of morphine-induced side effects including tolerance and hyperalgesia, and low dose of naltrexone could present an easy way to modulate this detrimental cascade.^[1]^[2]

Jan M. Keppel Hesselink, MD, PhD, october 2010

Referenties

[1]: Horvath RJ, DeLeo JA. | Morphine enhances microglial migration through modulation of P2X4 receptor signaling. | J Neurosci. | 2009 Jan 28;29(4):998-1005.

[2]: Wang HY, Friedman E, Olmstead MC, Burns LH. | Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in mu opioid receptor-G protein coupling and Gbetagamma signaling. | Neuroscience. | 2005;135(1):247-61.