FIGURE 5.10 Summary of responses to drugs and spontaneous behaviors in μ, δ, and κ opioid receptor knockout mice. Responses to drugs are shown on the left with drugs indicated; behaviors in the absence of drugs are shown on the right. ↓, strongly reduced or abolished. ↑, increased. →, unchanged. ↓→, unchanged or decreased depending on the experimental conditions. Abbreviation: THC, Δ9-tetrahydrocannabinol. [Modified with permission from Gaveriaux-Ruff C, Kieffer BL. Opioid receptor genes inactivated in mice: the highlights. Neuropeptides, 2002, (36), 62–71.]
A focal point for the involvement of the nucleus accumbens in opioid reward was the observation that selective destruction of the neurons themselves in the nucleus accumbens blocked cocaine, heroin, and morphine self-administration. Similarly, lesions of the ventral pallidum blocked both heroin and cocaine self-administration. Lesions of the pedunculopontine tegmental nucleus also blocked intravenous heroin self-administration. These studies suggest that neurons in the nucleus accumbens mediate the acute reinforcing properties of opioids and involve the processing of a circuit that includes not only the nucleus accumbens but also the ventral pallidum and pedunculopontine nucleus.
Withdrawal/Negative Affect Stage
One contribution to the intoxication associated with opioids reflects their ability to block the affective dimension of pain. The analgesic effects of opioids are caused by direct inhibition of nociceptive activity that ascends from the dorsal horn of the spinal cord to the brain circuitry associated with pain and also by activation of pain control circuits that descend from the midbrain via the rostral ventromedial medulla to the dorsal horn of the spinal cord. Endogenous opioid peptides and their receptors are highly localized to both the ascending and descending pain control circuits (Figure 5.12; for further reading, see Shurman et al., 2010).
FIGURE 5.11 Sagittal section through a representative rodent brain illustrating the pathways and receptor systems implicated in the acute reinforcing actions of opioids. Opioids activate opioid receptors in the ventral tegmental area, nucleus accumbens, and amygdala via direct actions or interneurons. Opioids facilitate the release of dopamine (red) in the nucleus accumbens via an action either in the ventral tegmental area or the nucleus accumbens, but also are hypothesized to activate elements independent of the dopamine system. Endogenous cannabinoids may interact with postsynaptic elements in the nucleus accumbens involving dopamine and/or opioid peptide systems. The blue arrows represent the interactions within the extended amygdala system hypothesized to have a key role in opioid reinforcement. AC, anterior commissure; AMG, amygdala; ARC, arcuate nucleus; BNST, bed nucleus of the stria terminalis; Cer, cerebellum; C-P, caudate putamen; DMT, dorsomedial thalamus; FC, frontal cortex; Hippo, hippocampus; IF, inferior colliculus; LC, locus coeruleus; LH, lateral hypothalamus; N Acc., nucleus accumbens; OT, olfactory tract; PAG, periaqueductal gray; RPn, reticular pontine nucleus; SC, superior colliculus; SNr, substantia nigra pars reticulata; VP, ventral pallidum; VTA, ventral tegmental area. [Taken with permission from Koob GF, Le Moal M. Neurobiology of Addiction. Academic Press, London, 2006.]