dynorphins and Abdominal-Pain

Opioid receptor screening of a conopeptide library led to a novel selective κ-opioid agonist peptide (conorphin T). Intensive medicinal chemistry, guided by potency, selectivity, and stability assays generated a pharmacophore model supporting rational design of highly potent and selective κ-opioid receptor (KOR) agonists (conorphins) with exceptional plasma stability. Conorphins are defined by a hydrophobic benzoprolyl moiety, a double arginine sequence, a spacer amino acid followed by a hydrophobic residue and a C-terminal vicinal disulfide moiety. The pharmacophore model was supported by computational docking studies, revealing receptor-ligand interactions similar to KOR agonist dynorphin A (1-8). A conorphin agonist inhibited colonic nociceptors in a mouse tissue model of chronic visceral hypersensitivity, suggesting the potential of KOR agonists for the treatment of chronic abdominal pain. This new conorphine KOR agonist class and pharmacophore model provide opportunities for future rational drug development and probes for exploring the role of the κ-opioid receptor.

Topics: Abdominal Pain; Analgesics; Animals; CHO Cells; Conus Snail; Cricetinae; Cricetulus; Cyclic AMP; Dynorphins; High-Throughput Screening Assays; Hypersensitivity; Male; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Neurons, Afferent; Peptide Library; Rats; Rats, Wistar; Receptors, Opioid, kappa; Structure-Activity Relationship

The role of bradykinin (BK) receptors in activating and sensitizing peripheral nociceptors is well known. Recently, we showed that spinal dynorphin was pronociceptive through direct or indirect BK receptor activation. Here, we explored the potential role of BK receptors in pain associated with persistent pancreatitis in rats.. Experimental pancreatitis and abdominal hypersensitivity were induced by intravenous administrations of dibutyltin dichloride (DBTC). [des-Arg-Leu]BK (B1 antagonist) and HOE 140 (B2 antagonist) were given by intraperitoneal or intrathecal injection. Dynorphin antiserum was given intrathecally. Reverse transcription-polymerase chain reaction was used to detect spinal mRNA for BK receptors.. Dibutyltin dichloride-induced pancreatitis upregulated B1 and B2 mRNA in the thoracic dorsal root ganglion and B2, but not B1, in the pancreas. No changes in spinal B1 or B2 mRNA were observed. Intraperitoneal or intrathecal administration of HOE 140 dose dependently abolished DBTC-induced abdominal hypersensitivity, whereas [des-Arg-Leu]BK was without effect by either route of administration. Antiserum to dynorphin (intrathecal) abolished DBTC-induced hypersensitivity.. These results suggest that blockade of peripheral or spinal BK B2 receptors may be an effective approach for diminishing pain associated with pancreatitis. Moreover, it is suggested that spinal dynorphin may maintain pancreatitis pain through direct or indirect activation of BK B2 receptors in the spinal cord.

Topics: Abdominal Pain; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B1 Receptor Antagonists; Bradykinin B2 Receptor Antagonists; Dynorphins; Ganglia, Spinal; Gene Expression; Immune Sera; Injections, Intraperitoneal; Injections, Intravenous; Injections, Spinal; Male; Organotin Compounds; Pain; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Reverse Transcriptase Polymerase Chain Reaction; Spinal Cord

We investigated whether central pain mechanisms including the endogenous antinociceptive system are involved in functional abdominal pain--that is, abdominal pain without abnormal findings at routine examinations. beta-Endorphin, met-enkephalin immunoreactivity, and dynorphin immunoreactivity were measured in cerebrospinal fluid (CSF) from nine patients with long-lasting functional abdominal pain and nine pain-free controls undergoing minor surgery while under spinal analgesia. Furthermore, pain sensitivity was evaluated with an ischaemic pain test comparing 21 functional abdominal pain patients with two control groups: 1) 24 patients with organic abdominal pain due to duodenal ulcer, gallstone, or urinary tract calculi, and 2) 13 healthy pain-free controls. The CSF beta-endorphin concentration was significantly decreased in the functional abdominal pain group as compared with nine matched controls (P = 0.01). Met-enkephalin and dynorphin immunoreactivities were normal. This part of the investigation was suspended after nine patients had been tested, because of post-lumbar-puncture headache. With regard to pain sensitivity, no significant difference between the three groups was shown, but subdivision of the functional abdominal pain group showed that individuals with pain and no symptoms of irritable bowel syndrome (IBS) were significantly more sensitive to pain than functional abdominal pain patients with IBS and healthy controls (P = 0.04).

Topics: Abdominal Pain; Adolescent; Adult; Aged; beta-Endorphin; Dynorphins; Enkephalin, Methionine; Female; Humans; Male; Middle Aged; Pain Threshold