The Peripheral Versus Central Antinociception of a Novel Opioid Agonist: Acute Inflammatory Pain in Rats

Abstract

Opioid analgesics devoid of central side effects are unmet medical need in the treatment of acute pain (e.g. post-operative pain). Recently, we have reported on 14-O-methylmorphine-6-O-sulfate (14-O-MeM6SU), a novel opioid agonist of high efficacy producing peripheral antinociception in subchronic inflammatory pain in certain doses. The present study focused on the antinociceptive effect of 14-O-MeM6SU compared to morphine in formalin test of an early/acute (Phase I) and late/tonic (Phase II) pain phases. Subcutaneous 14-O-MeM6SU (253-1012 nmol/kg) and morphine (3884-31075 nmol/kg) dose dependently reduced the pain behaviors of both phases. Co-administered naloxone methiodide (NAL-M), a peripherally acting opioid antagonist, abolished the antinociceptive effect of 506 nmol/kg 14-O-MeM6SU. On the other hand, the effects of 14-O-MeM6SU (1012 nmol/kg) and morphine (15538 nmol/kg) were only partially affected by NAL-M, indicating the contribution of CNS to antinociception. Locally injected test compounds into formalin treated paws caused antinociception in both phases. Locally effective doses of test compounds were also injected into contralateral paws. Morphine showed effects in both phases, 14-O-MeM6SU in certain doses failed to produce antinociception in either phase. A NAL-M reversible systemic dose of 14-O-MeM6SU and the lowest systemic effective dose of morphine were evaluated for their sedative effects following isoflurane-induced sleeping (righting reflex). In contrast to morphine, 14-O-MeM6SU in certain antinociceptive doses showed no impact on sleeping time. These data highlight that high efficacy opioids of limited CNS penetration in certain doses mitigate somatic and inflammatory pain by targeting MOR at the periphery.

The Antinociceptive Activities of Certain NSAIDS Combinations in Murine Orofacial Test

“…On the other hand, this automat-ed technique can be he formalin test, especially considered for the detection of analgesic drugs. From a general point of view, the NSAIDs used are in agreement with previous studies showing that opioids with restricted penetration into the CNS can reduce somatic and inflammatory pain by acting at the peripheral level [13][14][15].…”

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

“…At the present, we speculate that in the rat tail-flick test, which is an acute thermal pain model and MORs are not undertaken to substantial changes related to their number, the peripheral MOR reserve is not large enough for C6SU to produce stronger analgesic effect. Therefore, based on the above, we further extended our studies to examine the effect of 14-OMeC6SU compared to C6SU in animal pain model whereas the MORs reserve is significantly up-regulated [7,42,43]. Thus, CFA-induced inflammatory pain model suits the prerequisite condition for partial agonists-like C6SU in the present work-because ours and other research groups have reported on increased peripheral MOR expression in the inflamed paw in this model [37].…”

“…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.…”

Synthesis, Biological, and Structural Explorations of New Zwitterionic Derivatives of 14-O-Methyloxymorphone, as Potent μ/δ Opioid Agonists and Peripherally Selective Antinociceptives

“…The restricted capability to enter the CNS of compounds 2 – 5 was earlier demonstrated experimentally employing a commonly used pharmacological approach. 35,39,60,61 Antinociceptive effects of 2 – 5 in pain models of thermal nociception (tail-flick test) 45 and inflammatory hyperalgesia in the rat (the formalin test and carrageenan-induced hyperalgesia) 46,49 after systemic sc administration were completely blocked by sc naloxone methiodide, an opioid antagonist that does not cross the BBB. 27 Furthermore, naloxone methiodide completely antagonized antinociceptive effects of 6β-Gly-substituted 2b in the mouse eye wiping behavioral test for trigeminal nociception following systemic ip administration.…”