The objective of this manuscript is to summarize studies that demonstrate that the immune system participates in the expression of opiate withdrawal. Five groups of animals were used: 1. Chronic morphine control group; 2. The immune system was ablated in morphine-dependent rats; 3. In morphine-dependent animals the immune system was ablated and followed by reconstitution of the immune system from intact normal donor animals; 4.The immune system was ablated prior to chronic morphine exposure; and, 5. The immune system in morphine-naïve animals was ablated followed by immune component reconstitution from donor animals and then exposed to chronic morphine. All of the chronic morphine exposure animals were injected with 1.0 mg/kg naloxone to precipitate the behavioral withdrawal symptoms. In the first group, naloxone precipitated the classical behavioral syndrome; in groups 2 and 4 withdrawal symptoms were significantly attenuated and eliminated in some animals; and, in groups 3 and 5 naloxone injection resulted in severe withdrawal behavior. These experiments demonstrated that the immune system participates in opiate withdrawal expression and suggest the use of immunotherapy to control the opioid epidemic.

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