Accumulating evidence suggests that the neuropeptide substance P (SP) and its principal receptor neurokinin 1 (NK1) play a specific role in the behavioral response to opioids and stress that may help to initiate and maintain addictive behavior. In animal models, the NK1 receptor is required for opioids to produce their rewarding and motivational effects. SP neurotransmission is also implicated in the behavioral response to stress and in the process of drug sensitization, potentially contributing to vulnerability to addiction or relapse. However, SP neurotransmission only plays a minor role in opioid-mediated antinociception and the development of opioid tolerance. Moreover, the effects of SP on addiction-related behavior are selective for opioids and evidence supporting a role in the response to cocaine or psychostimulants is less compelling. This review will summarize the effects of SP neurotransmission on opioid-dependent behaviors and correlate them with potential contributing neural pathways. Specifically, SP neurotransmission within components of the basal forebrain particularly the nucleus accumbens and ventral pallidum as well as actions within the ascending serotonin system will be emphasized. In addition, cellular- or network-level interactions between opioids and SP signaling that may underlie the specificity of their relationship will be reviewed.
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