endomorphin-2 and Nociceptive-Pain

Activation of the mu-opioid receptor provides the gold standard for pain relief, but most opioids used clinically have adverse effects that have contributed to an epidemic of overdose deaths. We recently characterized mu-opioid receptor selective endomorphin (EM) analogs that provide potent antinociception with reduction or absence of a number of side effects of traditionally prescribed opioids including abuse liability, respiratory depression, motor impairment, tolerance, and inflammation. The current study explores the effectiveness of these EM analogs relative to morphine in four major pain models by intrathecal as well as intravenous administration in male Sprague Dawley rats and subcutaneous administration in male CD-1 mice. In the spared nerve injury model of neuropathic pain, mechanical allodynia and mechanical hyperalgesia were assessed with von Frey and Randall-Selitto tests, respectively. In the paw incision model of postoperative pain, von Frey testing was used to assess mechanical allodynia and thermal hyperalgesia was evaluated with Hargreaves testing. In the Complete Freund's Adjuvant model of inflammatory pain, thermal hyperalgesia was assessed using Hargreaves testing. In CD-1 mice, visceral pain was assessed with the acetic acid writhing test. In all cases, EM analogs had equal or greater potency and longer duration of action relative to morphine. The data suggest that EM analogs, particularly analog 4 (ZH853), could provide effective therapy for a diverse spectrum of pain conditions with low risk of adverse side effects compared with currently used opioids such as morphine.. Novel EM analogs show equal or greater potency and effectiveness relative to morphine in multiple pain models. Together with substantially reduced side effects, including abuse liability, the compounds show promise for addressing the critical need for effective pain relief as well as reducing the opioid overdose epidemic.

Topics: Analgesics, Opioid; Animals; Disease Models, Animal; Hyperalgesia; Inflammation; Injections, Intravenous; Injections, Spinal; Male; Mice; Morphine; Neuralgia; Nociceptive Pain; Oligopeptides; Pain, Postoperative; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Visceral Pain

C-terminal esterification of opioid peptides may change their opioid activities due to the modified physicochemical properties. In the present study, the pharmacological activities of C-terminal esterified endomorphin-2 (EM-2) analogs 1-3 were characterized by in vitro metabolic stability and octanol/buffer distribution assays. Also, the antinociceptive profiles in the radiant heat paw withdrawal test and related side effects of these analogs were determined. Our results showed that all three analogs significantly increased the metabolic stability and lipophilicity. Moreover, analogs 1-3 displayed potent antinociceptive activities after intracerebroventricular (i.c.v.) administration. Analogs 1 and 3 exhibited about 2-fold higher antinociception than EM-2, and differential opioid mechanisms were involved. In addition, EM-2 at 50 μmol/kg failed to produce any significant antinociceptive activity after subcutaneous (s.c.) administration, whereas equimolar dose of analogs 1-3 produced significant analgesic effects. Analog 3 showed the highest antinociceptive activity after systemic administration, which was consistent with its in vitro stability and lipophilicity. We further evaluated the antinociceptive tolerance of analogs 1-3. In acute tolerance test, analogs 1-3 shifted the dose-response curves rightward by only 1.4-3.2 fold as determined by tolerance ratio, whereas EM-2 by 5.6-fold, demonstrating reduced antinociceptive tolerance. Also, analogs 1 and 2 decreased chronic antinociceptive tolerance by central and peripheral administration of drugs. In particular, analogs 3 displayed insignificant chronic antinociceptive tolerance. Furthermore, analogs 1-3 were less prone to induce gastrointestinal side effects at analgesic doses. The present investigation gave the evidence that C-terminal esterified modifications of EM-2 will facilitate the development of novel opioid analgesics with reduced side effects.

Topics: Analgesics, Opioid; Animals; Catheters, Indwelling; Colon; Drug Stability; Drug Tolerance; Esterification; Gastrointestinal Transit; Hot Temperature; Male; Mice; Molecular Structure; Nociceptive Pain; Oligopeptides

Interactions between exogenous and endogenous opioids are not commonly investigated as a basis for sexually dimorphic opioid analgesia. We investigated the influence of spinal endomorphin 2 (EM2), an endogenous mu-opioid receptor (MOR) ligand, on the spinal antinociception produced by intrathecally administered opioids. Activation of spinal MORs facilitated spinal EM2 release. This effect was sexually dimorphic, occurring in males but not in females. Although activational effects of testosterone were required for opioid facilitation of spinal EM2 release in males, the absence of this facilitation in females did not result from either insufficient levels of testosterone or mitigating effects of estrogens. Strikingly, in males, the contribution of spinal EM2 to the analgesia produced by intrathecally applied MOR agonists depended on their analgesic efficacy relative to that of EM2. Spinal EM2 released by the higher efficacy MOR agonist sufentanil diminished sufentanil's analgesic effect, whereas EM2 released by the lower efficacy morphine had the opposite effect on spinal morphine antinociception. Understanding antithetical contributions of endogenous EM2 to intrathecal opioid antinociception not only enlightens the selection of opioid medications for pain management but also helps to explain variable sex dependence of the antinociception produced by different opioids, facilitating the acceptance of sexually dimorphic antinociception as a basic tenet.. The male-specific MOR-coupled enhancement of spinal EM2 release implies a parallel ability to harness endogenous EM2 antinociception. The inferred diminished ability of females to utilize the spinal EM2 antinociceptive system could contribute to their greater frequency and severity of chronic pain syndromes.

Topics: Analgesics, Opioid; Animals; Castration; Estrogens; Estrous Cycle; Female; Hot Temperature; Injections, Spinal; Male; Morphine; Nociceptive Pain; Oligopeptides; Physical Stimulation; Radioimmunoassay; Rats, Sprague-Dawley; Receptors, Opioid, mu; Sex Characteristics; Spinal Cord; Sufentanil; Testosterone