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RPEP-00053 · 1987

Repeated Brain Stimulation for Pain Relief Led to Tolerance That Could Be Overcome

Electrical stimulation of the periaqueductal grey (PAG, a brain region that controls pain) initially produced strong pain relief in rats. With repeated stimulation, this relief gradually disappeared. The tolerance was not from opioid depletion. Brain levels of beta-endorphin, met-enkephalin, and dynorphin were unchanged in tolerant rats compared to controls. It was not a learned (conditioned) response either. Tolerant rats exposed to all the cues associated with stimulation showed no compensatory pain increase. And repeated exposure to the cues without stimulation did not restore pain relief. The tolerance behaved exactly like drug tolerance: the dose-response curve shifted right (needed more stimulation for the same effect), it was reversed by naloxone, and it recovered spontaneously over time. Tolerant rats also showed cross-tolerance to morphine, confirming the same opioid receptor system was involved. Rats showed no signs of stress during the protocol: normal body weight, food intake, temperature, adrenal weight, and hormone levels.

Millan, M J; Członkowski, A; Herz, A · Animal Study

RPEP-00054 · 1987

A New Opioid Substance in Human Spinal Fluid Was Linked to Pain Status

Human cerebrospinal fluid (CSF) from pain-free surgery patients contained Peak B at a concentration equivalent to about 1.4 picomoles of morphine per milliliter. Injected into mouse brains, Peak B produced dose-dependent pain relief at 0.06 and 0.12 picomoles of morphine equivalents. Naloxone (an opioid blocker) reversed this effect, confirming it works through opioid receptors. In a muscle tissue assay (mouse vas deferens), Peak B's activity was blocked by low naloxone concentrations but not high ones. This unusual pattern suggests it interacts with opioid receptors differently than known opioids. Most surprisingly, Peak B was not destroyed by trypsin or alpha-chymotrypsin, protein-digesting enzymes that break down all known opioid peptides. This means Peak B is either not a peptide or has an unusual structure that protects it from enzymes.

Miller, B E; Lipman, J J; Byrne, W L · In Vitro

RPEP-00059 · 1987

Peripheral Opioid Receptors in the Gut Can Independently Slow Digestion

Peripheral mu-opioid receptors in the gut can independently slow gastrointestinal transit. The peptide agonist PL017 slowed gut transit at 0.37 mg/kg but did not produce pain relief until 30 mg/kg, about 80 times higher. This proves gut mu receptors work independently of brain receptors. Delta and kappa opioid receptors in the gut also slowed transit, but less powerfully than mu receptors. The key finding: a peptide opioid antagonist that cannot cross the blood-brain barrier blocked morphine's gut-slowing effect without reducing its painkilling activity. This pharmacological separation means constipation and pain relief work through different receptor populations (gut vs brain).

Shook, J E; Pelton, J T; Hruby, V J; Burks, T F · Animal Study

RPEP-00081 · 1988

Inflammation Raised Spinal Dynorphin and Changed Pain Sensitivity

Within 24 hours of inflammation, dynorphin increased specifically in the ipsilateral (same-side) dorsal horn of the spinal cord. Met-enkephalin, leu-enkephalin, and opioid receptor densities did not change. The inflamed paw showed pronounced supersensitivity to morphine's painkilling effect against pressure pain, starting at 24 hours and increasing at 1 week. Opioid antagonists (naloxone and the kappa-preferring MR 2266) made the pain worse, suggesting endogenous opioids were already partially controlling the pain. By 3-5 weeks, inflammation had spread to the opposite paw. Dynorphin was now elevated bilaterally and in the cervico-thoracic cord. Met-enkephalin and leu-enkephalin also rose bilaterally. Adrenal glands were enlarged and plasma beta-endorphin was elevated, signs of chronic stress. No changes in mu, delta, or kappa receptor density were found at any time point.

Millan, M J; Członkowski, A; Morris, B; Stein, C; Arendt, R; Huber, A; Höllt, V; Herz, A · Animal Study

RPEP-00088 · 1988

Cutting Any Peripheral Nerve Caused Brain-Wide Opioid Peptide Changes

Regardless of which nerve was cut (right or left sciatic, both sciatic, right brachial plexus, saphenous, or sural), the same brain-wide pattern emerged. Beta-endorphin decreased significantly in all brain areas except the striatum. Met-enkephalin increased in all brain areas and in the affected spinal cord segments. Substance P, somatostatin, and dynorphin were unaffected. The changes appeared within 24 hours of surgery and persisted for at least 4 months, indicating a long-lasting reorganization of the opioid system. There was no lateralization: unilateral nerve cuts produced bilateral brain changes. This means local nerve damage triggers a global brain response. Serotonergic drugs normalized beta-endorphin levels, suggesting the serotonin system mediates the opioid changes after nerve injury.

Panerai, A E; Sacerdote, P; Brini, A; Bianchi, M; Mantegazza, P · Animal Study

RPEP-00089 · 1988

Two Mouse Strains Had Opposite Stress Pain Relief Despite Similar Opioid Systems

DBA mice had higher baseline pain thresholds than C57 mice. But C57 mice showed much greater stress-induced analgesia (pain relief from stress). The opioid systems differed genetically: DBA mice had significantly more dynorphin in the hypothalamus and neurointermediate pituitary. C57 mice had lower KD values (better affinity) for spinal mu receptors but higher KD (lower affinity) for cerebral kappa receptors. Under stress, the two strains activated different opioid systems. C57 mice: beta-endorphin decreased in hypothalamus and increased in neurointermediate pituitary lobe. DBA mice: dynorphin decreased in hypothalamus and beta-endorphin increased in the anterior pituitary. Both strains showed spinal cord dynorphin decreases under stress.

Przewłocka, B; Vetulani, J; Lasoń, W; Dziedzicka, M; Silberring, J; Castellano, C; Przewłocki, R · Animal Study

RPEP-00090 · 1988

Low-Dose Enkephalin Blocked Substance P Pain Without Producing Direct Pain Relief

Intrathecal (spinal cord) met-enkephalin at low doses markedly reduced the aversive behavior caused by intrathecal substance P. At these same low doses, met-enkephalin produced no measurable analgesia in the tail-flick pain test. Met-enkephalin needed much higher doses to produce general analgesia. Beta-endorphin and dynorphin-(1-17) were different. They blocked substance P-induced behavior and produced general analgesia at roughly the same doses. There was no separation between the two effects. This suggests met-enkephalin has a specific, preferential interaction with substance P-mediated pain signaling in the spinal cord, separate from its general painkilling effects.

Sakurada, T; Takahashi, K; Sakurada, S; Kisara, K; Folkesson, R; Terenius, L · Animal Study

RPEP-00223 · 1992

Why Some Heart Attacks Are Painless: The Role of Natural Opioid Levels

Transient plasma beta-endorphin elevation in painful AMI (Group II, n=16) that normalized when pain ceased. No changes in painless AMI (Group I, n=12). Met-enkephalin and dynorphin unchanged in both.

Bernardi, P; Fontana, F; Pich, E M; Spampinato, S; Canossa, M · Cross Sectional

RPEP-00383 · 1996

BPC-157 Protects the Stomach Against Damage from Stress, Alcohol, NSAIDs, and Capsaicin

BPC-157 provided strong gastroprotection against four distinct injury types (stress, ethanol, NSAID, capsaicin neurotoxicity), suggesting a broad protective mechanism involving sensory nerve pathways.

Sikirić, P; Seiwerth, S; Grabarević, Z; Rucman, R; Petek, M; Jagić, V; Turković, B; Rotkvić, I; Mise, S; Zoricić, I; Gjurasin, M; Konjevoda, P; Separović, J; Ljubanović, D; Artuković, B; Bratulić, M; Tisljar, M; Jurina, L; Buljat, G; Miklić, P; Marović, A · Animal Study

RPEP-00389 · 1996

Protecting Dynorphin from Breakdown Extends Its Pain-Relieving Effects

Peptidase inhibitors significantly prolonged the antinociceptive effect of intrathecally administered dynorphin A (0.5-2 nmol) and dynorphin B (2-8 nmol) in the formalin test.

Tan-No, K; Taira, A; Sakurada, T; Inoue, M; Sakurada, S; Tadano, T; Sato, T; Sakurada, C; Nylander, I; Silberring, J; Terenius, L; Kisara, K · Animal Study

RPEP-00499 · 1998

How Electroacupuncture Triggers the Body's Natural Painkilling Peptides

Low-frequency (2 Hz) electroacupuncture activates endorphin/enkephalin systems (mu/delta receptors), while high-frequency (100 Hz) activates dynorphin systems (kappa receptors), with combined frequencies providing additive analgesia.

Ulett, G A; Han, S; Han, J S · Review

RPEP-00609 · 2000

Two Natural Opioid Peptides Relieve Pain Through Different Brain Pathways

Endomorphin-2 produces analgesia through both direct mu-opioid receptor activation and indirect dynorphin A release activating kappa receptors via descending pain pathways, while endomorphin-1 uses only the mu pathway.

Ohsawa, M; Mizoguchi, H; Narita, M; Chu, M; Nagase, H; Tseng, L F · Animal Study

RPEP-00648 · 2001

A Common Gene Variant in the Opioid Receptor Dramatically Weakens Pain Signaling

The N40D polymorphism in the human mu-opioid receptor severely impaired beta-endorphin-stimulated G-protein coupling and downstream signaling, potentially explaining ~10% of the population's altered pain sensitivity and opioid drug response.

Befort, K; Filliol, D; Decaillot, F M; Gaveriaux-Ruff, C; Hoehe, M R; Kieffer, B L · In Vitro