Translational approach to the pathophysiology of panic disorder: Focus on serotonin and endogenous opioids

- Two neurochemical hypotheses try to explain why panic patients are more vulnerable to experience panic attacks.
- Panic patients may have deficient serotonergic inhibition of neurons that organize proximal defense.
- Panic patients may lack opioid buffering, leading to heightened sensitivity to suffocation and separation anxiety.
- Serotonin interacts with opioids in the dorsal periaqueductal gray, allowing reconciliation between the above hypotheses.
- Exogenous opioids might be used as alternative or adjunctive medication in the treatment of drug-resistant panic patients.

Panic patients experience recurrent panic attacks. Two main neurochemical hypotheses have been proposed to explain this vulnerability. The first suggests that panic patients have deficient serotonergic inhibition of neurons localized in the dorsal periaqueductal gray matter of the midbrain that organizes defensive reactions to cope with proximal threats as well as of sympathomotor control areas of the rostral ventrolateral medulla that generate neurovegetative symptoms of the panic attack. The second proposes that endogenous opioids buffer panic attacks in normal subjects, and their deficit results in heightened sensitivity to suffocation and separation anxiety in panic patients. Experimental results obtained in rat models of panic indicate that serotonin interacts synergistically with endogenous opioids in the dorsal periaqueductal gray through 5-HT1A and μ-opioid receptors to inhibit proximal defense and, supposedly, panic attacks. These findings allow reconciliation of the serotonergic and opioidergic hypotheses of panic pathophysiology. They also indicate that endogenous opioids are likely to participate in the panicolytic action of antidepressants and suggest that exogenous opioids may be useful for treating panic patients resistant to conventional pharmacotherapy.