Loss of Peripheral Morphine Analgesia Contributes to the Reduced Effectiveness of Systemic Morphine in Neuropathic Pain

Abstract

It is well known that the analgesic potency of morphine is reduced in neuropathic pain. In this study, we demonstrate that the decreased effectiveness of systemic morphine in neuropathic pain might be caused by the loss of morphine analgesia at the periphery. When given s.c. or i.t., the dose-response curves for morphine analgesia in Hargreaves thermal test were shifted rightward in partial sciatic nerve-injured mice compared with control sham-operated mice. The dose-response curves for i.c.v. morphine analgesia, however, were unchanged in nerve-injured mice, indicating no decrease in morphine potency at the supraspinal level. On the other hand, the dosedependent analgesia produced by intraplantar (i.pl.) morphine in sham-operated mice almost completely disappeared in nerve-injured mice. With the more sensitive algogenic-induced nociceptive flexion test, significant reduction in the analgesic potency of systemic morphine was observed for bradykinin (BK) nociception in nerve-injured mice, and the analgesic effect of i.pl. morphine against BK nociception in sham-operated mice disappeared in nerve-injured mice. In immunohistochemical experiments, we found that, under normal state, -opioid receptors (MOPs) were mainly expressed in small-diameter unmyelinated dorsal root ganglion (DRG) neurons and colocalized with bradykinin B2 receptors. When we examined MOP expression in the DRG of nerve-injured mice, we observed a drastic decrease in MOP expression. Altogether, these data suggest that the lower potency of systemic morphine in neuropathic pain could be at least partly caused by the decreased MOP expression in DRG and subsequent loss of peripheral morphine analgesia in such a condition.

Morphine peripheral analgesia depends on activation of the PI3Kγ/AKT/nNOS/NO/K ATP signaling pathway

“…S8 A and B). Indeed, after peripheral nerve lesions, there is a consistent reduction in opioid-receptor expression in primary nociceptive neurons (28). Recently, it was shown that during neuropathic states, there is a reduction of K ATP currents in rat primary sensitive neurons, probably by a defect in upmodulation of these currents by NO and the Ca 2+ /Calmodulin/ CAMKII pathway (24,29).…”

“…This mechanism could not be immediately extended to neuropathic pain, because the peripheral analgesic effectiveness of morphine is greatly abrogated during neuropathic pain states (28) (Fig. S8 A and B).…”

Nerve Injury Diminishes Opioid Analgesia through Lysine Methyltransferase-mediated Transcriptional Repression of μ-Opioid Receptors in Primary Sensory Neurons

“…MORs expressed at primary sensory neurons and their central terminals in the spinal dorsal horn are essential for the analgesic effects of opioids (8 -10). Peripheral nerve injury reduces the expression level of MORs in the dorsal root ganglion (DRG), contributing to the loss of opioid analgesic efficacy in neuropathic pain (6,11,12). However, the epigenetic mechanisms by which nerve injury leads to diminished MOR expression in the DRG remain unclear.…”

“…In patients with neuropathic pain, however, the analgesic potency of MOR agonists is reduced (3,4). The opioid effects are also diminished in animal models of neuropathic pain (5)(6)(7). MORs expressed at primary sensory neurons and their central terminals in the spinal dorsal horn are essential for the analgesic effects of opioids (8 -10).…”

Role of peripheral μ‐opioid receptors in arthritis: Are they potential targets for therapy?

“…The lack of efficacy of opioids under neuropathic conditions has been previously shown and attributed to receptor down-regulation both centrally and peripherally (8), while such changes have not been observed during inflammation. In this issue of Arthritis & Rheumatism, Li and colleagues (9) report on a novel finding in an experimental rat model of chronic monarthritis.…”