Mechanism of Analgesia

Pain control by opioids needs to be considered in the context of brain circuits modulating analgesia and the functions of the various types of receptors in these circuits.^[19] It has been well established that the analgesic effects of opioids arise from their ability to inhibit directly the ascending transmission of nociceptive information from the spinal cord dorsal horn^[1] and to activate pain control circuits that descend from the midbrain, via the rostral ventromedial medulla (RVM), to the spinal cord dorsal horn.^[2]

Immunohistochemical studies and in situ hybridization analysis have demonstrated that opioid receptors are expressed in various areas in the central nervous system (CNS).^[5] These include the amygdala, the mesencephalic reticular formation, the periaqueductal gray matter (PAG), and the rostral ventral medulla. However, the role of the opioid receptors in all of these areas has not been completely clarified.

Microinjection of morphine into the PAG or direct electrical stimulation of this area produces analgesia that can be blocked by naloxone. Opioid actions at the PAG influence the RVM, which in turn modulates nociceptive transmission in the dorsal horn of the spinal cord through the action of the descending inhibition pathway. Thus, opioids not only produce analgesia by direct actions on the spinal cord but also produce analgesia by neurally mediated action in the region separated from the site of opioid administration.

The distribution of opioid receptors in descending pain control circuits indicates substantial overlap between μ and κ receptors. Interactions between the κ receptor and the μ receptor may be important for modulating nociceptive transmission from higher nociceptive centers as well as in the spinal cord dorsal horn. The μ receptor produces analgesia within descending pain control circuits, at least in part, by the removal of γ-aminobutyric acid (GABA)ergic inhibition of RVM-projecting neurons in the PAG and spinally projecting neurons in the RVM.^[19] The actions of μ-receptor agonists are invariably analgesic, whereas those of κ-receptor agonists can be either analgesic or antianalgesic. The pain-modulating effects of the κ-receptor agonists in the brainstem appear to oppose those of μ-receptor agonists.^[20]

Local spinal mechanisms, in addition to descending inhibition, underlie the analgesic action of opioids. In the spinal cord, opioids act at synapses either presynaptically or post-synaptically. Opioid receptors are abundantly expressed in the substantia gelatinosa, where substance P release from the primary sensory neuron is inhibited by opioids.

There is significant opioid-receptor ligand binding, and little detectable receptor mRNA expression in the spinal cord dorsal horn, but high levels of opioid-receptor mRNA in dorsal root ganglia. This distribution suggests that the actions of opioid-receptor agonists relevant to analgesia at the spinal level may be predominantly presynaptic. It is well known that opioids decrease the pain-evoked release of tachykinins from primary afferent nociceptors. However, it was demonstrated that at least 80% of tachykinin signaling in response to noxious stimulation remains intact after the intrathecal administration of large doses of opioids.^[21] These results suggest that, while opioid administration may reduce tachykinin release from primary afferent nociceptors, this reduction has little functional impact on the actions of tachykinins on postsynaptic pain-transmitting neurons.

The actions of opioids in bulbospinal pathways are critical to their analgesic efficacy. It is clear that opioid actions in the forebrain contribute to analgesia, because decerebration prevents analgesia when rats are tested for pain sensitivity using the formalin test,^[22] and microinjection of opioids into several forebrain regions are analgesic in this test.^[23] Analgesia induced by systemic administration of morphine in both the tail flick and formalin tests was disrupted either by lesioning or reversibly inactivating the central nucleus of the amygdala, demonstrating that opioid actions in the forebrain contribute to analgesia in measures of tissue damage as well as acute phasic nociception. ^{[24] [25]}

Opioids may also produce analgesia through peripheral mechanisms. ^[26] Immune cells infiltrating the inflammation site may release endogenous opioid-like substances, which act on the opioid receptors located on the primary sensory neuron.^[26] However, other studies do not support this conclusion.^{[27] [28]}