naltrindole and Neuralgia

Tricyclic antidepressants are used clinically as first-line treatments for neuropathic pain. Opioid receptors participate in this pain-relieving action, and preclinical studies in receptor-deficient mice have highlighted a critical role for δ-, but not μ-opioid receptors. In this study, we investigated whether κ-opioid (KOP) receptors have a role in the antiallodynic action of tricyclic antidepressants.. We used a model of neuropathic pain induced by unilateral sciatic nerve cuffing. In this model, the mechanical allodynia was evaluated using von Frey filaments. Experiments were conducted in C57BL/6J mice, and in KOP receptor-deficient mice and their wild-type littermates. The tricyclic antidepressant nortriptyline (5 mg · kg(-1)) was delivered twice a day for over 2 weeks. Agonists and antagonists of opioid receptors were used to test the selectivity of the KOP receptor antagonist norbinaltorphimine (nor-BNI) in mice with neuropathic pain.. After 12 days of treatment, nortriptyline relieved neuropathic allodynia in both wild-type and KOP receptor-deficient mice. Surprisingly, acute nor-BNI reversed the effect of nortriptyline in both wild-type and KOP receptor-deficient mice. Further experiments showed that nor-BNI action was selective for KOP receptors at a late time-point after its administration (8 h), but not at an early time-point, when it may also interact with δ-opioid (DOP) receptors.. KOP receptors are not necessary for the effect of a tricyclic antidepressant against neuropathic allodynia. These findings together with previous data indicate that the DOP receptor is the only opioid receptor that is necessary for the antiallodynic action of antidepressants.

Topics: Animals; Antidepressive Agents, Tricyclic; Male; Mice, Inbred C57BL; Mice, Knockout; Naltrexone; Neuralgia; Nortriptyline; Receptors, Opioid, delta; Receptors, Opioid, kappa; Sciatic Nerve

Spinal cord stimulation (SCS) is used for the management of chronic intractable neuropathic pain. While used clinically, it is unclear if SCS produces its effects by activation of opioid receptors. The current study aimed to determine if endogenous opioids mediate the analgesia produced by SCS at different frequencies of stimulation in rats with neuropathic pain [spared nerve injury (SNI) model].. Mechanical withdrawal thresholds of the paw were tested before and after 6 h of SCS at different frequencies (4 Hz, 60 Hz and sham) given daily for 4 days at 90% motor threshold 2 weeks after SNI. Rats were given naloxone (3-10 mg/kg/h), naltrindole (1 mg/kg/h) or were made tolerant to morphine (375 g pellets daily), and effects of SCS were tested.. A dose of 3 mg/kg/h naloxone prevented the analgesia produced by 4-Hz, but not 60-Hz, SCS; 10 mg/kg/h prevented the analgesia produced by 60-Hz SCS. Naltrindole prevented the analgesia produced by 60-Hz, but not 4-Hz, SCS. In morphine-tolerant rats, 4-Hz SCS had no effect on withdrawal thresholds, but 60-Hz SCS remained effective as seen by increased withdrawal thresholds.. These results suggest that both 4- and 60-Hz SCS, in part, work through opioid receptor mechanisms, with 4-Hz SCS activating μ-opioid receptors while 60-Hz SCS activated δ-opioid receptors.

Topics: Analgesics, Opioid; Animals; Hyperalgesia; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Neuralgia; Pain Measurement; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Spinal Cord; Spinal Cord Stimulation

Tricyclic antidepressants (TCAs) are among the first line treatments clinically recommended against neuropathic pain. However, the mechanism by which they alleviate pain is still unclear. Pharmacological and genetic approaches evidenced a critical role of delta-opioid receptors (DORs) in the therapeutic action of chronic TCA treatment. It is however unclear whether mu-opioid receptors (MORs) are also necessary to the pain-relieving action of TCAs. The lack of highly selective MOR antagonists makes difficult to conclude based on pharmacological studies. In the present work, we thus used a genetic approach and compared mutant mice lacking MORs and their wild-type littermates. The neuropathy was induced by unilateral sciatic nerve cuffing. The threshold for mechanical response was evaluated using von Frey filaments. MOR-deficient mice displayed the same baseline for mechanical sensitivity as their wild-type littermates. After sciatic nerve cuffing, both wild-type and MOR-deficient mice displayed an ipsilateral mechanical allodynia. After about 10 days of treatment, nortriptyline suppressed this allodynia in both wild-type and MOR-deficient mice. MORs are thus not critical for nortriptyline action against neuropathic pain. An acute injection of the DOR antagonist naltrindole induced a relapse of neuropathic allodynia in both wild-type and MOR-deficient mice, thus confirming the critical role of DORs in nortriptyline action. Moreover, morphine induced an acute analgesia in control and in neuropathic wild-type mice, but was without effect in MOR-deficient mice. While MORs are crucial for morphine action, they are not critical for nortriptyline action. Our results highlight the functional difference between DORs and MORs in mechanisms of pain relief.

Topics: Adrenergic Uptake Inhibitors; Analysis of Variance; Animals; Male; Mice; Mice, Knockout; Morphine; Naltrexone; Narcotic Antagonists; Neuralgia; Nortriptyline; Pain Measurement; Receptors, Opioid, mu

The current study investigated the roles of various subtypes of opioid receptors expressed in the thalamic nucleus submedius (Sm) in inhibition of mirror-image allodynia induced by L5/L6 spinal nerve ligation in rats. Morphine was microinjected into the Sm, which produced a dose-dependent inhibition of mirror-image allodynia; this effect was antagonized by pretreatment with non-selective opioid receptor antagonist naloxone. Microinjections of endomorphin-1 (mu-receptor agonist), or [D-Ala(2), D-Leu(5)]-enkephalin (DADLE, delta-/mu-receptor agonist), also inhibited mirror-image allodynia, and these effects were blocked by the selective mu-receptor antagonist, beta-funaltrexamine hydrochloride. The DADLE-induced inhibition, however, was not influenced by the delta-receptor antagonist naltrindole. The kappa-receptor agonist, spiradoline mesylate salt, failed to alter the mirror-image allodynia. These results suggest that Sm opioid receptor signaling is involved in inhibition of mirror-image allodynia; this effect is mediated by mu- (but not delta- and kappa-) opioid receptors in the rat model of neuropathic pain.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Enkephalin, Leucine-2-Alanine; Hyperalgesia; Ligation; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Neuralgia; Oligopeptides; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Spinal Nerves; Thalamic Nuclei

It has been widely recognized that chronic pain could cause physiological changes at supraspinal levels. The delta-opioidergic system is involved in antinociception, emotionality, immune response and neuron-glia communication. In this study, we show that mice with chronic pain exhibit anxiety-like behavior and an increase of astrocytes in the cingulate cortex due to the dysfunction of cortical delta-opioid receptor systems. Using neural stem cells cultured from the mouse embryonic forebrain, astrocyte differentiation was clearly observed following long-term exposure to the selective delta-opioid receptor antagonist, naltrindole. We also found that micro-injection of either activated astrocyte or astrocyte-conditioned medium into the cingulate cortex of mice aggravated the expression of anxiety-like behavior. Our results indicate that the chronic pain process promotes astrogliosis in the cingulate cortex through the dysfunction of cortical delta-opioid receptors. This phenomenon may lead to emotional disorders including aggravated anxiety under chronic pain-like state.

Topics: Animals; Anxiety Disorders; Astrocytes; Brain Tissue Transplantation; Cells, Cultured; Cerebral Cortex; Chronic Disease; Culture Media, Conditioned; Disease Models, Animal; Gliosis; Gyrus Cinguli; Male; Mice; Mice, Inbred C57BL; Naltrexone; Narcotic Antagonists; Neuralgia; Pain, Intractable; Peripheral Nervous System Diseases; Receptors, Opioid, delta; Sciatic Neuropathy; Stem Cells