Opiate analgesics can act through three different types of opioid receptors, called mu, delta, and kappa. Morphine, the most widely used opiate analgesic, acts primarily via activation of the mu opioid receptor located in the central nervous system (CNS). This CNS action induces pain relief but is also associated with a wide array of CNS-mediated side effects including sedation, respiratory depression and abuse liability. As a way to avoid these undesirable CNS effects, there has been an effort to develop opioids that selectively activate (agonist) peripheral opioid receptors such as kappa receptors, present on sensory nerves, outside the central nervous system.1
Kappa opioid receptors
The kappa-opioid receptors (KOR) are widely expressed in the central nervous system and peripheral tissues. Peripheral kappa receptors represent kappa opioid receptors localized on sensory nerves, outside of the central nervous system.2 Substantial evidence has shown that activation of KOR by agonists and endogenous opioid peptides in vivo may produce a strong analgesic effect that is free from the abuse potential and the adverse side effects of mu-opioid receptor (MOR) agonists, such as morphine. In addition, activation of the KOR has also been shown to exert an inverse effect on morphine-induced adverse actions, such as tolerance, reward, and impairment of learning and memory. Therefore, the KOR has received much attention in the effort to develop alternative analgesics to MOR agonists and agents for the treatment of drug addiction.3
Mu opioid receptors are located on the pre-synaptic terminals of nociceptive afferents as well as the dendrites of post-synaptic neurons.4 Endogenous opioid peptides and exogenous opioid alkaloids regulate nociceptive transmission at key points in the pain modulatory system. Modulation occurs through a combination of pre-synaptic and post–synaptic actions.
Nociceptive stimulation of sensory neurons causes calcium ions to enter pre-synaptic sensory terminals, triggering neurotransmitter release. Exogenous opiates reduce the release of neurotransmitters by activating pre-synaptic opioid receptors. Activated receptors restrict calcium ion channels in sensory terminals. Reduced calcium ion influx inhibits the release of neurotransmitters from the dorsal horn terminals of primary afferent nociceptors. This causes analgesia as nociceptive transmission from pre-synaptic to post–synaptic neurons is reduced.5
Opiates also produce analgesia by activating potassium ion channels post–synaptic opioid receptors. This causes potassium ion efflux from the post–synaptic neuron. The efflux of potassium ions causes a build up of a negative charge on the inner surface of the neuron. This hyper-polarization decreases the amplitude of the post–synaptic firing of the neuron resulting in a decrease in signaling to pain centers in the brain.67
Delta-opioid receptor (DOR) agonists have a modest analgesic effect when microinjected into the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) under basal conditions but show significant antinociceptive potency during chronic inflammation. Injection of the ORL1 agonist nociceptin (orphanin FQ) into the RVM interferes with the antinociceptive effect of mu-opioid agonists administered systemically or microinjected into the PAG, but it also attenuates the hyperalgesia associated with acute opioid withdrawal. This apparent paradox can be understood in the context of the RVM circuitry and is explained by the fact that nociceptin inhibits the firing of both pain-inhibiting and pain-facilitating neurons in the RVM.8
1http://www.caratherapeutics.com/terminology.shtml 2http://www.caratherapeutics.com/terminology.shtml 3Wang YH et al. The role of κ-opioid receptor activation in mediating antinociception and addiction. Acta Pharmacologica Sinica (2010) 31: 1065–1070. 2010. 4Jessell TM, Kelly DD. Pain and analgesia, p397. 5Wall and Melzack’s Textbook of Pain, 5th Edition p128. 2010. 6Ballantyne. Management of Pain., p1173. 2009. 7Wall and Melzack’s Textbook of Pain, 5th Edition p430. 2010. 8Heinricher MM, Fields HL. Central Nervous System Mechanisms of Pain Modulation. Wall and Melzack’s Textbook of Pain, Chapter 8. 2013.