Breathing stimulants for reversal of opioid induced respiratory depression

[plumbus-nine]

Potent synthetic opioids are an important cause of death in the United States' opioid epidemic, and a breathing stimulant may have utility in treating opioid overdose. We hypothesized that sufentanil-induced respiratory depression may be reversed by breathing stimulant administration. METHODS: Using nose-only plethysmography and arterial blood analysis, we compared effects of several breathing stimulants in reversing sufentanil-induced respiratory depression in conscious rats. We studied taltirelin (1 mg/kg IV), PKTHPP (5 mg/kg IV), CX717 (30 mg/kg IV), BIMU8 (1 mg/kg IV), A85380 (30 mcg/kg IV), 8-OH-DPAT (150 mcg/kg IV/IM), and used sufentanil (10 mcg/kg IV). RESULTS: By plethysmography (in % baseline, mean{plus minus}SEM), taltirelin restored ventilation in sufentanil-treated rats (from 50{plus minus}5 to 102{plus minus}8%) by increased breathing rates (from 80{plus minus}4 to 160{plus minus}12%). By arterial blood analysis, however, taltirelin did not correct hypoxia, decreased hypercarbia only after 45 min, and worsened metabolic acidosis (base excess from +0{plus minus}1 to -7{plus minus}1 mEq/L). Additionally, taltirelin increased exhaled carbon dioxide, an estimate of oxygen consumption, by up to 64%. PKTHPP, CX717, BIMU8, and A85380 failed to significantly change ventilation or arterial blood values in sufentanil-treated rats. 8-OH-DPAT, however, improved ventilation (from 54{plus minus}8 to 92{plus minus}10%), reversed hypercarbia (from 64{plus minus}6 to 47{plus minus}2 mmHg) and shortened time-to-righting from 43{plus minus}4 to 15{plus minus}1 min in sufentanil-treated rats placed supine. CONCLUSION: Taltirelin has limited therapeutic potential as its ventilatory effects are offset by metabolic acidosis, possibly from increased oxygen consumption. At the doses studied, PKTHPP, CX717, BIMU8, and A85380 have limited effects in reversing sufentanil-induce respiratory depression; 8-OH-DPAT, however, warrants further study. Source

Taltirelin (marketed under the tradename Ceredist) is a thyrotropin-releasing hormone (TRH) analog, which mimics the physiological actions of TRH, but with a much longer half-life and duration of effects,[1] and little development of tolerance following prolonged dosing.[2] It has nootropic,[3] neuroprotective[4] and analgesic effects.[5]

So one could just take talitrelin and happily overdose on heroin?? As it is not an antagonist, let alone inverse agonist like naloxone, and even analgesic itself - will and how will talitrelin influence an opioid experience? Is this purely scientific or something which could prevent deaths?

Oh, and this:

Opioid overdose intervention by naloxone, a high affinity receptor antagonist, reverses opioid-induced respiratory depression (OIRD) and analgesia by displacing opioids. Systemic naloxone stimulates release of the hypothalamic neuropeptide oxytocin, which has analgesic properties and participates in cardiorespiratory homeostasis. To test the hypothesis that oxytocin can reverse OIRD, we assessed the rescue potential of graded doses (0, 0.1, 2, 5, 10, 50 nmol/kg, i.v) of oxytocin to counter fentanyl (60 nmol/kg, i.v.)-induced depression of neural inspiration indexed by recording phrenic nerve activity (PNA) in anesthetized (urethane/α-chloralose), vagotomized, and artificially ventilated rats. Oxytocin dose-dependently rescued fentanyl OIRD by almost immediately reversing PNA burst arrest (P=0.0057) and restoring baseline burst frequency (P=0.0016) and amplitude (P=0.0025) at low, but not high doses, resulting in inverted bell-shaped dose-response curves. Oxytocin receptor antagonism (40 nmol/kg, i.v.) prevented oxytocin reversal of OIRD (Arrest: P=0.0066, Frequency: P=0.0207, Amplitude: P=0.0022). Vasopressin 1A receptor (V1aR) antagonism restored high-dose oxytocin efficacy to rescue OIRD (P=0.0170 - P<0.0001), resulting in classic sigmoidal dose-response curves, and prevented (P=0.0135) transient hypertension from V1aR cross-activation (P=0.0275). Alone, vasopressin (5 nmol/kg, i.v.) failed to reverse fentanyl respiratory arrest (P=0.6184). The non-peptide oxytocin receptor agonist WAY-267464 (75 nmol/kg, i.v.), which has V1aR antagonist properties, quickly reversed fentanyl OIRD (P<0.0001), with rapid recovery of PNA frequency (P=0.0011) and amplitude (P=0.0044) without adverse hemodynamic consequences (P=0.9991). Findings indicate that peptide and non-peptide agonist activation of oxytocin receptors without V1aR cross-activation rescues fentanyl OIRD. Oxytocin receptor agonists could be lifesaving resuscitation agents that enhance rather than interrupt opioid analgesia.

Significance Statement Oxytocin receptor activation produces analgesia. Here, we demonstrate that activation by the FDA-approved agonist oxytocin and the non-peptide partial agonist WAY-267464 can each reverse fentanyl cardiorespiratory depression. Selective targeting of oxytocin receptors for resuscitation from opioid overdose, alone or in combination with an opioid antagonist, could eliminate or attenuate negative side effects associated with traditional opioid receptor antagonism.

Unfortunately these aren't sci-hubable yet.