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Development of morphine analgesic tolerance is modulated by spinal P2X7 receptors

Leduc-Pessah HL, Weilinger N, Fan C, Thompson R, Trang T (2014) Development of morphine analgesic tolerance is modulated by spinal P2X7 receptors. Neuroscience 2014 Abstracts 327.08. Society for Neuroscience, Washington, DC.

Summary: Growing evidence suggests that microglia, which are immune cells in the central nervous system, are causally involved in the development of opioid analgesic tolerance. Here, we investigated the importance of spinal microglial ATP-gated P2X7 receptors (P2X7Rs) in morphine tolerance. In adult male Sprague Dawley rats, we found that seven days of systemic morphine treatment resulted in a progressive decline in morphine anti-nociception and a loss in analgesic potency, the two key features of analgesic tolerance. The development of morphine tolerance correlated with an increase in spinal Iba-1 expression, a marker indicative of microglial activation. To assess whether spinal microglia are required for morphine tolerance, we depleted microglia in the spinal cord of morphine treated rats using intrathecal injections of a saporin-conjugated antibody to Mac1 (Mac1-saporin). We found that Mac1-saporin attenuated the decline in morphine anti-nociception in rats that received chronic morphine treatment. In contrast, intervention with Mac1-saporin failed to restore morphine analgesia in rats with established tolerance. Thus, spinal microglia are causally involved in the development, but they are not required for the ongoing expression, of morphine tolerance. In addition, we found that P2X7R protein expression was markedly increased in the spinal cord of morphine tolerant animals. Pharmacological blockade of P2X7Rs with the selective antagonist A740003 attenuated the development of tolerance but did not reverse established tolerance. In BV2 microglial cells, repeated morphine treatment increased total P2X7R protein expression, an effect recapitulated by the mu-opioid receptor agonist DAMGO, and suppressed by the mu-receptor antagonist, CTAP. The morphine-induced increase in P2X7R protein expression was concomitant with a potentiation of BzATP evoked P2X7R calcium responses and inward current. Collectively, our findings suggest that spinal microglia are causally involved in the development, but not expression, of morphine analgesic tolerance. We also determined that the expression and function of P2X7R in microglia are critically modulated by mu-opioid receptors.

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