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Review
. 2015 Oct 14;35(41):13879-88.
doi: 10.1523/JNEUROSCI.2711-15.2015.

Pain and Poppies: The Good, the Bad, and the Ugly of Opioid Analgesics

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Free PMC article
Review

Pain and Poppies: The Good, the Bad, and the Ugly of Opioid Analgesics

Tuan Trang et al. J Neurosci. .
Free PMC article

Abstract

Treating pain is one of the most difficult challenges in medicine and a key facet of disease management. The isolation of morphine by Friedrich Sertürner in 1804 added an essential pharmacological tool in the treatment of pain and spawned the discovery of a new class of drugs known collectively as opioid analgesics. Revered for their potent pain-relieving effects, even Morpheus the god of dreams could not have dreamt that his opium tincture would be both a gift and a burden to humankind. To date, morphine and other opioids remain essential analgesics for alleviating pain. However, their use is plagued by major side effects, such as analgesic tolerance (diminished pain-relieving effects), hyperalgesia (increased pain sensitivity), and drug dependence. This review highlights recent advances in understanding the key causes of these adverse effects and explores the effect of chronic pain on opioid reward.

Significance statement: Chronic pain is pervasive and afflicts >100 million Americans. Treating pain in these individuals is notoriously difficult and often requires opioids, one of the most powerful and effective classes of drugs used for controlling pain. However, their use is plagued by major side effects, such as a loss of pain-relieving effects (analgesic tolerance), paradoxical pain (hyperalgesia), and addiction. Despite the potential side effects, opioids remain the pharmacological cornerstone of modern pain therapy. This review highlights recent breakthroughs in understanding the key causes of these adverse effects and explores the cellular control of opioid systems in reward and aversion. The findings will challenge traditional views of the good, the bad, and the ugly of opioids.

Figures

Figure 1.
Figure 1.
Spinal mechanisms of opioid analgesia. A, In the spinal dorsal horn, nociceptive signals encoded by action potentials trigger the release of nociceptive transmitters, such as substance P (SP), calcitonin gene-related peptide (CGRP), and l-glutamate (Glu). Second-order projection neurons then relay this information from the spinal cord to the brain, where the information is disseminated and decoded to produce the emotional and sensory experiences of pain. B, Opioids produce their analgesic effects by inhibiting spinal nociceptive transmission. On presynaptic nerve terminals, opioids reduce cAMP signaling and suppress activity of voltage-gated calcium channels, which inhibits release of nociceptive transmitters. On postsynaptic neurons, opioids activate inward potassium channels to cause hyperpolarization of ascending projection neurons. Opioids also produce analgesia by activating descending inputs from the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM), which are key components of the descending inhibitory pain pathways. In these supraspinal structures, opioid-mediated disinhibition of GABAergic interneurons leads to activation of monoamine-containing descending neurons that suppress nociceptive transmission in the spinal dorsal horn. CGRPR, Calcitonin gene-related peptide receptor; NK-1, neurokinin-1 receptor.
Figure 2.
Figure 2.
Microglial-mediated disruption of chloride homeostasis in spinal lamina I neurons gates morphine hyperalgesia. In response to chronic morphine treatment, microglia residing in the spinal cord adopt a reactive state characterized by μ receptor-dependent upregulation of P2X4R expression. Activation of P2X4R causes the release of BDNF, which signals to downregulate the potassium-chloride cotransport KCC2, resulting in a dysregulation of chloride homeostasis in spinal lamina I pain signaling neurons. The P2X4R–BDNF–KCC2 pathway is not only critical for the paradoxical hyperalgesic effect of morphine but also for pain hypersensitivity after peripheral nerve injury.
Figure 3.
Figure 3.
Model of microglial-mediated altered reward circuitry. As a consequence of chronic opioid exposure or chronic pain, microglial activation occurs in many areas of the CNS, including brain regions involved in reward such as the VTA. It is hypothesized that gliosis triggers a reorganization of reward circuitry such that microglia change EGABA in GABAergic neurons within the VTA. A, In the naive state, these neurons tonically inhibit mesolimbic dopaminergic neurons projecting to the NAc. B, In chronic pain states, activated microglia release BDNF. This in turn causes disruption of EGABA via downregulation of the K+/Cl transporter KCC2 protein levels and activity. The loss of KCC2 causes a disruption of Cl homeostasis in GABAergic neurons, resulting in these neurons being more depolarized. Consequently, activation of GABAA receptors on these GABAergic neurons results in their depolarization rather than hyperpolarization because of a net inward anion (Cl/HCO3) current (that is normally outward). An increase in the excitability of GABAergic neurons results in an increase in GABA release and augmentation of the inhibitory tone on dopaminergic neurons, leading to less dopamine release in the NAc. DA, Dopamine.

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