u-50488 and Constriction--Pathologic

Activation of opioid receptors on peripheral sensory neurons has the potential for safe pain control, as it lacks centrally mediated side effects. While this approach often only partially suppressed neuropathic pain in animal models, opioids were mostly applied to animal paws although neuropathy was induced at the nerve trunk. Here we aimed to identify the most relevant peripheral site of opioid action for efficient antinociception in neuropathy. On days 2 and 14 following a chronic constriction injury (CCI) of the sciatic nerve in mice, we evaluated dose and time relationships of the effects of μ-, δ-, and κ-opioid receptor agonists injected either at the CCI site or intraplantarly (i.pl.) into the lesioned nerve-innervated paw, on spontaneous paw lifting and heat and mechanical hypersensitivity (using Hargreaves and von Frey tests, respectively). We found that neither agonist diminished spontaneous paw lifting, despite the application site. Heat hypersensitivity was partially attenuated by i.pl. μ-receptor agonist only, while it was improved by all three agonists applied at the CCI site. Mechanical hypersensitivity was slightly diminished by all agonists administered i.pl., whereas it was completely blocked by all opioids injected at the CCI site. These antinociceptive effects were opioid receptor type-selective and site-specific. Thus, opioids might not be effective against spontaneous pain, but they improve heat and mechanical hypersensitivity in neuropathy. Importantly, efficient alleviation of hypersensitivity is governed by peripheral opioid receptors at the injured nerve trunk rather than at its peripheral terminals. Identifying the primary action site of analgesics is important for the development of adequate pain therapies.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Animals; Behavior, Animal; Constriction, Pathologic; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Foot; Hot Temperature; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Nerve Endings; Neuralgia; Pain Measurement; Peripheral Nerve Injuries; Peripheral Nerves; Physical Stimulation; Receptors, Opioid

The effect of repeated contralateral administration of the kappa-opioid receptor agonist U-50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methanesulfonate) on nociceptive behaviour was investigated and compared with ipsilateral and bilateral treatments in a rat model of peripheral unilateral neuropathy (chronic constriction of the common sciatic nerve). Administration of 0.3 mg U-50,488H into the contralateral hindpaw on days 6 and 10 after induction of mononeuropathy increased hindpaw withdrawal latency to mechanical but not to thermal stimulation compared to saline-treated rats. No difference in pain-related behaviour was found between different peripheral (contralateral, ipsilateral and bilateral) treatments with 0.3 mg U-50,488H. Autotomy behaviour was reduced for 6 weeks after sciatic nerve ligation in rats treated contralaterally with the opioid receptor agonist. Antinociceptive effects of contralaterally administered U-50,488H were abolished by the peripherally acting opioid receptor antagonist naloxone methiodide. Our findings indicate that contralateral treatment with U-50,488H attenuates nociceptive behaviour in mononeuropathic rats. These antinociceptive effects are mediated via peripheral opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Animals; Behavior, Animal; Constriction, Pathologic; Functional Laterality; Hot Temperature; Male; Pain; Peripheral Nervous System Diseases; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Sciatic Nerve; Self Mutilation