At the receptor level, two mechanisms have been implicated in the within-system changes that may contribute to acute tolerance: receptor desensitization and receptor internalization. The role of desensitization in opioid tolerance remains controversial because tolerance develops at doses that do not produce desensitization. Opioid receptors are coupled to second messenger systems, and they may be involved in acute tolerance. μ and δ receptors but not κ receptors can also undergo rapid agonist-mediated internalization via endocytosis, in which cells absorb these proteins by surrounding them. Endogenous ligands (opioid peptides) cause rapid internalization, and others, such as morphine and oxycodone, do not, indicating that different intracellular events may play a role in the relative efficacy of opioids. A significant proportion of tolerance to opioids may involve recruitment of between-system neuroadaptations as outlined below for opioid withdrawal.

FIGURE 5.12 Pathways for the supraspinal processing of pain superimposed on key elements of addiction circuitry implicated in negative emotional states. Blue structures are involved in the “fast” processing of pain via the spinothalamic tract, and pain signals arrive indirectly in the amygdala. Pink structures are involved in the “fast” processing of pain via the spinal–parabrachial–amygdala pathway, and pain signals arrive directly in the amygdala. Yellow structures are involved in the “slower” cognitive processing of pain. Notice significant overlap of the supraspinal processing of pain and addiction in the amygdala. ACC, anterior cingulate cortex; AMG, amygdala; BNST, bed nucleus of the stria terminalis; DRG, dorsal root ganglion; DS, dorsal striatum; GP, globus pallidus; Hippo, hippocampus; Hyp, hypothalamus; Insula, insular cortex; OFC, orbitofrontal cortex; PAG, periaqueductal gray; PB, parabrachial nucleus; PPC, posterior parietal cortex; S1, S2, somatosensory cortex; SMA, supplementary motor area; Thal, thalamus; VS, ventral striatum. [Modified with permission from Blackburn-Munro G,Blackburn-Monro R. Pain in the brain: are hormones to blame? Trends in Endocrinology and Metabolism 2003, (14), 20–27.

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