Article

An altered spinal serotonergic system contributes to increased thermal nociception in an animal model of depression

Experimental Brain Research (Impact Factor: 2.17). 03/2014; 232(6). DOI: 10.1007/s00221-014-3871-7
Source: PubMed

ABSTRACT The olfactory bulbectomized (OB) rat, an animal model of chronic depression with comorbid anxiety, exhibits a profound dysregulation of the brain serotonergic signalling, a neurotransmission system involved in pain transmission and modulation. We here report an increased nociceptive response of OB rats in the tail flick test which is reverted after chronic, but not acute, administration of fluoxetine. Autoradiographic studies demonstrated down-regulation of 5-HT transporters ([(3)H]citalopram binding) and decreased functionality of 5-HT1A receptors (8-OH-DPAT-stimulated [(35)S]GTPγS binding) in the dorsal horn of the lumbar spinal cord in OB rats. Acute administration of fluoxetine (5-40 mg/kg i.p.) did not modify tail flick latencies in OB rats. However, chronic fluoxetine (10 mg/kg/day s.c., 14 days; osmotic minipumps) progressively attenuated OB-associated thermal hyperalgesia, and a total normalization of the nociceptive response was achieved at the end of the treatment with the antidepressant. In these animals, autoradiographic studies revealed further down-regulation of 5-HT transporters and normalization in the functionality of 5-HT1A receptors on the spinal cord. On the other hand, acute morphine (0.5-10 mg/kg s.c.) produced a similar analgesic effect in OB and sham and OB rats, and no changes were detected in the density ([(3)H]DAMGO binding) and functionality (DAMGO-stimulated [(35)S]GTPγS binding) of spinal μ-opioid receptors in OB rats before and after chronic fluoxetine. Our findings demonstrate the participation of the spinal serotonergic system in the increased thermal nociception exhibited by the OB rat and the antinociceptive effect of chronic fluoxetine in this animal model of depression.

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    ABSTRACT: Chronic pain and depression share a complex, reciprocal relationship. Furthermore, in addition to treating depression, antidepressants such as amitriptyline are a first-line treatment for chronic pain conditions, indicating possible common neural substrates underlying both depression and pain. However, there is a paucity of studies examining the effect of antidepressant treatment on nociceptive and neuropathic-pain responding in the presence of a depressive phenotype. The current study aimed to examine the effect of chronic amitriptyline administration on neuropathic pain-related behaviour and associated neuroinflammatory processes in the olfactory bulbectomised (OB) rat model of depression. Nociceptive responding to mechanical, innocuous cold or noxious heat stimuli in sham or OB rats was not altered by chronic amitriptyline administration. The induction of neuropathic pain following L5-L6 spinal nerve ligation (SNL) resulted in robust mechanical and cold allodynia and heat hyperalgesia in both sham and OB vehicle-treated animals. Chronic amitriptyline administration attenuated SNL-induced mechanical allodynia in both sham and OB rats at day 7 post-SNL, an effect which was enhanced and prolonged in OB rats. In comparison, chronic amitriptyline administration attenuated SNL-induced cold allodynia and heat hyperalgesia in sham, but not OB, rats. Evaluating the affective/motivational aspect of pain using the place escape avoidance paradigm revealed that OB-SNL rats exhibit reduced noxious avoidance behaviour when compared with sham-counterparts, an effect not altered by chronic amitriptyline administration. Chronic amitriptyline administration prevented the increased expression of GFAP, IL-10 and CCL5, and enhanced the expression of TNFα, in the prefrontal cortex of OB-SNL rats. In conclusion, these data demonstrate that chronic amitriptyline differentially alters somatic nociceptive responding following peripheral nerve-injury, depending on stimulus modality and the presence or absence of a depressive-like phenotype, an effect which may involve modulation of neuroinflammatory processes.
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