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Opioids are a class of endogenous, naturally occurring, and synthetic compounds that primarily provide analgesia. The effects of opioids are generated at an array of receptors found in peripheral, spinal cord, and brain tissues. Individual opioid receptors may be responsible for analgesia, muscle rigidity, depressed respiratory drive, bradycardia, hypotension, constipation, urinary retention, nausea, and sedation, to name several important clinical effects.

Pain is transmitted via a three-neuron system that originates at the periphery and ends at the cerebral cortex. At periphery tissues, noxious stimuli are mainly received and transmitted by A beta, A delta, and C fiber neurons. These first-order neurons synapse with second-order neurons in the dorsal horn of the spinal cord level. Second-order neurons travel up the spinal cord via the dorsal column and spinothalamic tract and synapse with third-order neurons at the thalamus, which then transmit signals to the cerebral cortex, the site of pain perception. Opioids exert their effects on receptors at all three levels of this system.


Tissue injury at peripheral tissue causes the release of many different chemical mediators responsible for pain and physical changes at the site of injury. A host of major pain-inducing mediators originate from activated cells at the site of injury.

  • Bradykinin—Originating from macrophages and plasma kininogen, this mediator activates nociceptors.

  • Serotonin—Originating from platelets, this mediator activates nociceptors.

  • Histamine—Originating from platelets and mast cells, this mediator causes vasodilation, edema, and pruritis.

  • Prostaglandin—Originating from the cyclooxygenase (COX) pathway, this mediator sensitizes nociceptors.

  • Leukotriene—Originating from the lipoxygenase pathway, this mediator sensitizes nociceptors.

  • H+ ions—Originating from tissue injury and ischemia, this mediator causes hyperalgesia associated with inflammation.

  • Cytokines (tumor necrosis factor [TNF], interleukins)—Originating from macrophages, these mediators sensitize nociceptors.

  • Adenosine—Originating from tissue injury, this mediator activates nociceptors and causes hyperalgesia.

  • Glutamate—Originating from injured nerve terminals, this mediator activates nociceptors.

  • Substance P—Originating from injured nerve terminals, this mediator activates macrophages and mast cells.

  • Nerve growth factor—Originating from macrophages, this mediator stimulates mast cells to release histamine and serotonin.

These pain mediators signal various receptors located throughout the three-neuron pain signal system. The transmitted signal travels to the cerebral cortex and is perceived as pain. Opioid therapy aims to block or attenuate a nociception signal by activating receptors that counter signal transmission. The major receptors activated by opioids are mu, delta, and kappa. These are G-coupled receptors, which carry the mediator-induced signal in conjunction with a second messenger such as cyclic adenosine monophosphate (cAMP). They are located at the periphery, the dorsal horn of the spinal cord, and finally the brainstem, thalamus, and cortex. At these locations, the three major mechanisms of action are:

  1. Inhibition of presynaptic Ca2+ influx, which depolarizes the cell and inhibits the release of neurotransmitters at the synaptic cleft.

  2. Increasing postsynaptic K+ efflux depolarizes and ...

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