Persistent Peripheral Inflammation Attenuates Morphine-Induced Periaqueductal Gray Glial Cell Activation and Analgesic Tolerance in the Male Rat

Morphine is among the most prevalent analgesics prescribed for chronic pain. However, prolonged morphine treatment results in the development of analgesic tolerance. An abundance of evidence has accumulated indicating that central nervous system glial cell activity facilitates pain transmission and opposes morphine analgesia. While the midbrain ventrolateral periaqueductal gray (vIPAG) is an important neural substrate mediating pain modulation and the development of morphine tolerance, no studies have directly assessed the role of PAG glia. Here we test the hypothesis that morphine-induced increases in vIPAG glial cell activity contribute to the development of morphine tolerance. As morphine is primarily consumed for the alleviation of severe pain, the influence of persistent inflammatory pain was also assessed. Administration of morphine, in the absence of persistent inflammatory pain, resulted in the rapid development of morphine tolerance and was accompanied by a significant increase in vIPAG glial activation. In contrast, persistent inflammatory hyperalgesia, induced by intraplantar administration of complete Freund's adjuvant (CFA), significantly attenuated the development of morphine tolerance. No significant differences were noted in vIPAG glial cell activation for CFA-treated animals versus controls. These results indicate that vIPAG glia are modulated by a persistent pain state, and implicate vIPAG glial cells as possible regulators of morphine tolerance. Perspective: The development of morphine tolerance represents a significant impediment to its use in the management of chronic pain. We report that morphine tolerance is accompanied by increased glial cell activation within the vIPAG, and that the presence of a persistent pain state prevented vIPAG glial activation and attenuated morphine tolerance. Published by Elsevier Inc. on behalf of the American Pain Society