Comprehensive Preclinical Assessment of Sensory, Functional, Motivational-Affective, and Neurochemical Outcomes in Neuropathic Pain: The Case of the Sigma-1 Receptor

Abstract

Chronic pain remains a major health problem and is currently facing slow drug innovation. New drug treatments should address not only the sensory-discriminative but also functional and motivational-affective components of chronic pain. In a mouse model of neuropathic pain induced by partial sciatic nerve ligation (PSNL), we analyzed sensory and functional-like outcomes by hindpaw mechanical stimulation and automated gait analysis (CatWalk). We characterized over time a reward-seeking task based on diminished motivation for natural reinforcers (anhedonic-like behavior). To differentiate the appetitive ("wanting") and consummatory ("liking") aspects of motivational behavior, we quantified the latency and number of approaches to eat white chocolate, as well as the eating duration and amount consumed. We explored a putative chronic paininduced dysregulation of monoamine function by measuring monoamine levels in the nucleus accumbens (NAc), a well-known brain reward area. Finally, we investigated the role of sigma-1 receptor (σ 1 R) modulation, a nonopioid target, in these multiple dimensions by genetic deletion and pharmacological dose−response studies. After 6 weeks, PSNL increased the approach latency and reduced the consumption of white chocolate in 20−25% of the mice, while around 50−60% had one or the other parameter affected independently. After 10 weeks, sham-operated mice also displayed anhedonic-like behavior. PSNL was associated with reduced extracellular baseline dopamine and increased norepinephrine in the NAc and with a suppression of increased dopamine and serotonin efflux in response to the rewarding stimulus. Genetic and pharmacological blockade of σ 1 R relieved these multiple alterations in nerve-injured mice. We comprehensively describe sensory, functional, and depression-like impairment of key components of motivated behavior associated with nerve injury. We provide a neurochemical substrate for the depressed mesocorticolimbic reward processing in chronic pain, with a potentially increased translational value. Our results also highlight σ 1 R for the therapeutic intervention of neuropathic pain.

Long-lasting reflexive and nonreflexive pain responses in two mouse models of fibromyalgia-like condition

“…Accordingly, other studies described a different time course of sensory and affective consequences of chronic pain. Affective ones develop later and last longer 70 .…”

Resilience to Pain-Related Depression in σ1 Receptor Knockout Mice Is Associated with the Reversal of Pain-Induced Brain Changes in Affect-Related Genes

“…Recently, we demonstrated that negative affective-like changes produced by sciatic nerve injury appeared later than sensory changes (hypersensitivity to mechanical stimuli in the hind paw) and lasted longer . In the study, we observed changes in functional (gait analysis using the catwalk system) and affective dimensions at 6 weeks (using a highly palatable food reward-seeking task) that were associated with imbalances in monoaminergic function in the nucleus accumbens.…”

“…Thus, in order to elucidate the underlying molecular mechanisms of the depressive resistant phenotype shown by σ 1 R –/– mice submitted to PSNL, we measured at week 6 postinjury the level of gene expression of important proteins involved in pain regulation and its associated affective disorders such as anxiety and depression at the central level. ,, We focus on identifying the altered expression of DAT and SERT as well as its corresponding rate-limiting enzymes, tyrosine hydroxylase (Th), and tryptophan hydroxylase 2 (Tph2). Additionally, we also analyzed the mRNA expression of BDNF, μ opioid receptor, and σ 1 R. Because sensory and affective changes were also observed in sham animals, we included naive animals in our study to better characterize the effects of surgery and direct sciatic nerve injury. ,, Assuming that the encoding of complex behavioral phenomena as depression induced by neuropathic pain involves coordinated gene expression in multiple brain regions, we analyzed, in the same experiment, transcription of genes across 10 structures associated with the limbic and mesolimbic systems.…”

Long-Lasting Nociplastic Pain Modulation by Repeated Administration of Sigma-1 Receptor Antagonist BD1063 in Fibromyalgia-like Mouse Models

“…Both reflexive and nonreflexive pain behaviors were measured before histological processing. Nonreflexive responses provide complementary information about the overall impact of the persistent sensory abnormality [ 73 , 74 ]. The effect of BD1063 and pregabalin on both anxiety- and depression-like behaviors described in either RIM6 or ASI models [ 7 ] were also evaluated by means of the light/dark box and the forced swimming test, respectively.…”