An interesting side effect of proglumide is that it enhances theanalgesia produced byopioid drugs,[5] and can prevent or even reverse the development oftolerance to opioid drugs.[6][7] This can make it a usefuladjuvant treatment to use alongside opioid drugs in the treatment of chronic pain conditions such as cancer, where opioid analgesics may be required for long periods and development of tolerance reduces clinical efficacy of these drugs.[8][9]
Proglumide has also been shown to act as aδ-opioid receptor (DOR) agonist, which may contribute to its analgesic effects.[10] However, other studies show that proglumide has low affinity to theμ-opioid receptor (MOR) and theκ-opioid receptor (KOR) (13% of MOR and 17% of KOR occupancy at 100 μM), but no affinity to DOR.[11] It is questionable whether this is clinically significant, since the concentration they used was very high, and the occupancies were low even at that point.[citation needed]
Proglumide also works as aplacebo effect amplifier for pain conditions. When injected visibly to a subject, its analgesic effect is bigger than a similarly administered placebo. When injected secretly, it does not have any effect, whereas standard pain drugs have an effect, even if they are administered without the subject's awareness.[12] The supposed mechanism is an enhancement of the neural pathways of expectation as a result of dopamine and endogenous opioids being suddenly released throughout numerous structures of the brain and spinal cord.[citation needed]
Theventral tegmental area is the structure believed to mediate proglumide's analgesic and euphoric effects, however dozens of areas with a wide range of physical and psychological functions are implicated in the mediation of the placebo effect (this accounts for proglumide's ability to produce physically measurable effects onvital signs such as heart rate, blood pressure, respiration rate, andtidal volume which cannot be accounted for by its clinically insignificant δ-opioid affinity.[citation needed]
^González-Puga C, García-Navarro A, Escames G, León J, López-Cantarero M, Ros E, Acuña-Castroviejo D (October 2005). "Selective CCK-A but not CCK-B receptor antagonists inhibit HT-29 cell proliferation: synergism with pharmacological levels of melatonin".Journal of Pineal Research.39 (3):243–250.doi:10.1111/j.1600-079X.2005.00239.x.PMID16150104.S2CID20187767.
^Bergemann W, Consentius K, Braun HE, Hirschmann H, Marowski B, Munck A, et al. (April 1981). "[Duodenal ulcer - multicenter double-blind study with proglumide]".Medizinische Klinik.76 (8):226–229.PMID7231338.
^Tariq M, Parmar NS, Ageel AM (May 1987). "Gastric and duodenal antiulcer and cytoprotective effects of proglumide in rats".The Journal of Pharmacology and Experimental Therapeutics.241 (2):602–607.PMID3572816.
^McCleane GJ (November 1998). "The cholecystokinin antagonist proglumide enhances the analgesic efficacy of morphine in humans with chronic benign pain".Anesthesia and Analgesia.87 (5):1117–1120.doi:10.1213/00000539-199811000-00025.PMID9806692.S2CID10735834.
^Rezvani A, Stokes KB, Rhoads DL, Way EL (1987). "Proglumide exhibits delta opioid agonist properties".Alcohol and Drug Research.7 (3):135–146.PMID3030338.
^Gaudreau P, Lavigne GJ, Quirion R (May 1990). "Cholecystokinin antagonists proglumide, lorglumide and benzotript, but not L-364,718, interact with brain opioid binding sites".Neuropeptides.16 (1):51–55.doi:10.1016/0143-4179(90)90029-X.PMID2174522.S2CID25646937.
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