Reduction of opioid withdrawal symptoms and opioid-induced hyperalgesia by subcutaneous sumatriptan reveals central neuromodulation

: Triptans are efficacious, largely prescribed antimigraine drugs but where and how they exert their therapeutic effect is debated. Because of the presumed impermeability of the blood brain barrier to triptans, a peripheral antimigraine effect of these drugs have been repeatedly proposed. Recent findings, however, indicate that triptans cross the blood brain barrier, and counteract central nociception in models of pronociceptive sensitization. Here, we investigated the effects of subcutaneous (s.c.) sumatriptan in models of opioid withdrawal and opioid-induced hyperalgesia, two conditions sustained by deranged descending facilitation by the rostral ventromedial medulla (RVM). We found that s.c. sumatriptan injection in morphine-dependent rats 30 min before naloxone-precipitated withdrawal reduced severity of withdrawal symptoms. We also found that at the time of naloxone injection sumatriptan reached contents of 294±19 and 371±30 pg/mg of tissue in the RVM and locus coeruleus, respectively. In keeping with data on morphine withdrawal, s.c. sumatriptan injections suppressed thermal hyperalgesia in rats undergoing repeated dosing of morphine. Sumatriptan affected neither behavioral signs in morphine-dependent rats unexposed to naloxone, nor the extent of the initial antinociceptive response to morphine. Overall, data suggest that peripherally injected sumatriptan reaches CNS concentrations sufficient to exert functional neuromodulation of brainstem regions involved in pronociceptive sensitization and nociplasticity. PERSPECTIVE: This article reports that sumatriptan reduces symptoms of morphine withdrawal and morphine-induced hyperalgesia. Data suggests that triptans exert their antinociceptive effects through central mechanisms.