New Morphine Analogs Produce Peripheral Antinociception within a Certain Dose Range of Their Systemic Administration

Abstract

Growing data support peripheral opioid antinociceptive effects, particularly in inflammatory pain models. Here, we examined the antinociceptive effects of subcutaneously administered, recently synthesized 14-O-methylmorphine-6-O-sulfate (14-O-MeM6SU) compared with morphine-6-O-sulfate (M6SU) in a rat model of inflammatory pain induced by an injection of complete Freund's adjuvant and in a mouse model of visceral pain evoked by acetic acid. Subcutaneous doses of 14-O-MeM6SU and M6SU up to 126 and 547 nmol/kg, respectively, produced significant and subcutaneous or intraplantar naloxone methiodide (NAL-M)-reversible antinociception in inflamed paws compared with noninflamed paws. Neither of these doses significantly affected thiobutabarbital-induced sleeping time or rat pulmonary parameters. However, the antinociceptive effects of higher doses were only partially reversed by NAL-M, indicating contribution of the central nervous system. In the mouse writhing test, 14-O-MeM6SU was more potent than M6SU after subcutaneous or intracerebroventricular injections. Both displayed high subcutaneous/intracerebroventricular ED50 ratios. The antinociceptive effects of subcutaneous 14-O-MeM6SU and M6SU up to 136 and 3043 nmol/kg, respectively, were fully antagonized by subcutaneous NAL-M. In addition, the test compounds inhibited mouse gastrointestinal transit in antinociceptive doses. Taken together, these findings suggest that systemic administration of the novel compound 14-O-MeM6SU similar to M6SU in specific dose ranges shows peripheral antinociception in rat and mouse inflammatory pain models without central adverse effects. These findings apply to male animals and must be confirmed in female animals. Therefore, titration of systemic doses of opioid compounds with limited access to the brain might offer peripheral antinociception of clinical importance.

Cyclic derivatives of morphiceptin possess anti-transit effect in the gastrointestinal tract and alleviate abdominal pain in mice

“…Similar results were reported for morphine-6-O-sulphate in several tests: the tail flick test, chronic constriction nerve injury hyperalgesia and allodynia, and formalin test [23]. On the contrary, the doses of morphine-6-O-sulphate required to alleviate visceral pain in acetic acid-induced writhing in mice were equal to doses that affect GI peristalsis [24]. Morphiceptin derivatives with β2-or β3-amino acids synthesized by Gach et al [21]: peptide 2 and peptide 4 exerted strong antinociceptive action in acetic acid writhing test in mice, the effect was comparable to morphiceptin (0.1 mg/kg, ip).…”

Comparisons of In Vivo and In Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6-O-sulfate and Codeine-6-O-sulfate

“…It is well known, that partial agonists show lower agonist activity than the higher efficacy opioid agonists when the MOR reserve is decreased [40]. Additionally, this pain model is widely used in opioid research to assess the contribution of the peripheral opioid receptors to antinociception [5,44]. Here we found that systemic administration of both 14-OMeC6SU and C6SU abolished the reduced pain threshold of the inflamed paws, indicating the antihyperalgesic effects of the test compounds.…”

“…In addition, pharmacological evidence has shown that opioids are also capable to produce antinociception by the activation of opioid receptors reside outside the central nervous system [4][5][6][7][8][9][10]. Indeed, opioid agonists that have been reported to induce peripheral antinociception display a prerequisite physiochemical property, a limited central nervous system (CNS) penetration [4,5,7]. Thus, over the last four decades many opioid research groups have undertaken the task of synthesis and pharmacological characterization of opioid compounds with limited CNS penetration and thereby inducing antinociception by activating opioid receptors at the periphery.…”

“…This chemical structure modification was carried out by the introduction of ionizable groups into the C-6 position such as sulfate, amino acids or guanido groups as described previously [6,[13][14][15][16][17][18][19][20][21]. Such compounds have been demonstrated to have reduced central side effects as well [5,21]. Extreme increase in the affinity, efficacy and analgesic activity was measured for 14-methoxy analogs of morphine or oxymorphone compared to the parent compounds [4,6,20,22,23].…”

Advances in the Physicochemical Profiling of Opioid Compounds of Therapeutic Interest

“…Since morphine derivatives possess a basic tertiary amino group, these compounds are zwitterionic at physiological pH values. Thus, these sulfate esters cannot cross the blood‐brain barrier, and consequently are good candidates to develop peripheral analgesic drugs …”