u-50488 and Peripheral-Nerve-Injuries

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 effects of intraperitoneal (I.P.), intracerebroventricular (ICV) and intrathecal (IT) opiates were studied in the rat neuropathic pain model of Kim and Chung. Dose dependent reduction of allodynia was observed after I.P. and ICV morphine, but not after IT morphine, IT or ICV c[D-pen2 D-pen5]enkephalin (DPDPE) (delta agonist), or IT or ICV U50488H (kappa agonist). The effects of ICV morphine were blocked by I.P. naloxone, but not by IT methysergide, phentolamine or 8-sulfophenyltheophylline. Catalepsy (immobility) was observed after IT, ICV and IT morphine but this was not reliably associated with a reduction of allodynia. I.P. and ICV morphine may thus reduce tactile allodynia via supraspinal, but not spinal, mu opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Analgesics, Opioid; Animals; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Injections, Intraperitoneal; Injections, Intraventricular; Injections, Spinal; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Pain; Peripheral Nerve Injuries; Pyrrolidines; Rats; Rats, Sprague-Dawley