Detection of cold pain, cold allodynia and cold hyperalgesia in freely behaving rats

BACKGROUND: Pain is elicited by cold, and a major feature of many neuropathic pain states is that normally innocuous cool stimuli begin to produce pain (cold allodynia). To expand our understanding of cold induced pain states we have studied cold pain behaviors over a range of temperatures in several animal models of chronic pain. RESULTS: We demonstrate that a Peltier-cooled cold plate with ± 1°C sensitivity enables quantitative measurement of a detection withdrawal response to cold stimuli in unrestrained rats. In naïve rats the threshold for eliciting cold pain behavior is 5°C. The withdrawal threshold for cold allodynia is 15°C in both the spared nerve injury and spinal nerve ligation models of neuropathic pain. Cold hyperalgesia is present in the spared nerve injury model animals, manifesting as a reduced latency of withdrawal response threshold at temperatures that elicit cold pain in naïve rats. We also show that following the peripheral inflammation produced by intraplantar injection of complete Freund's adjuvant, a hypersensitivity to cold occurs. CONCLUSION: The peltier-cooled provides an effective means of assaying cold sensitivity in unrestrained rats. Behavioral testing of cold allodynia, hyperalgesia and pain will greatly facilitate the study of the neurobiological mechanisms involved in cold/cool sensations and enable measurement of the efficacy of pharmacological treatments to reduce these symptoms

Effects of optogenetic stimulation of vasopressinergic retinal afferents on suprachiasmatic neurons

Physiological circadian rhythms are orchestrated by the hypothalamic suprachiasmatic nucleus (SCN). The activity of SCN cells is synchronised by environmental signals, including light information from retinal ganglion cells (RGCs). We recently described a population of vasopressin‐expressing RGCs (VP‐RGC) that send axonal projections to the SCN. To determine how these VP‐RGCs influence the activity of cells in the SCN, we used optogenetic tools to specifically activate their axon terminals within the SCN. Rats were intravitreally injected with a recombinant adeno‐associated virus to express the channelrhodopsin‐2 and the red fluorescent protein mCherry under the vasopressin promoter (VP‐ChR2mCherry). In vitro recordings in acute brain slices showed that approximately 30% of ventrolateral SCN cells responded to optogenetic stimulation with an increase in firing rate that progressively increased during the first 200 seconds of stimulation and which persisted after the end of stimulation. Finally, application of a vasopressin V1A receptor antagonist dampened the response to optogenetic stimulation. Our data suggest that optogenetic stimulation of VP‐RGC axons within the SCN influences the activity of SCN cells in a vasopressin‐dependent manner.The data that support the findings of this study are openly available at http://datashare.is.ed.ac.ukMedical Research Council. Grant Number: MR/M022838http://wileyonlinelibrary.com/journal/jne2020-12-01hj2020Immunolog

Delayed sympathetic dependence in the spared nerve injury (SNI) model of neuropathic pain

Background: Clinical and experimental studies of neuropathic pain support the hypothesis that a functional coupling between postganglionic sympathetic efferent and sensory afferent fibers contributes to the pain. We investigated whether neuropathic pain-related behavior in the spared nerve injury (SNI) rat model is dependent on the sympathetic nervous system. Results: Permanent chemical sympathectomy was achieved by daily injection of guanethidine (50 mg/kg s.c.) from age P8 to P21. SNI was performed at adulthood followed by 11 weeks of mechanical and thermal hypersensitivity testing. A significant but limited effect of the sympathectomy on SNI-induced pain sensitivity was observed. The effect was delayed and restricted to cold allodynia-like behavior: SNI-related cold scores were lower in the sympathectomized group compared to the control group at 8 and 11 weeks after the nerve injury but not before. Mechanical hypersensitivity tests (pinprick and von Frey hair threshold tests) showed no difference between groups during the study period. Concomitantly, pericellular tyrosine-hydroxylase immunoreactive basket structures were observed around dorsal root ganglia (DRG) neurons 8 weeks after SNI, but were absent at earlier time points after SNI and in sham operated controls. Conclusion: These results suggest that the early establishment of neuropathic pain-related behavior after distal nerve injury such as in the SNI model is mechanistically independent of the sympathetic system, whereas the system contributes to the maintenance, albeit after a delay of many weeks, of response to cold-related stimuli

Delayed sympathetic dependence in the spared nerve injury (SNI) model of neuropathic pain

BACKGROUND: Clinical and experimental studies of neuropathic pain support the hypothesis that a functional coupling between postganglionic sympathetic efferent and sensory afferent fibers contributes to the pain. We investigated whether neuropathic pain-related behavior in the spared nerve injury (SNI) rat model is dependent on the sympathetic nervous system. RESULTS: Permanent chemical sympathectomy was achieved by daily injection of guanethidine (50 mg/kg s.c.) from age P8 to P21. SNI was performed at adulthood followed by 11 weeks of mechanical and thermal hypersensitivity testing. A significant but limited effect of the sympathectomy on SNI-induced pain sensitivity was observed. The effect was delayed and restricted to cold allodynia-like behavior: SNI-related cold scores were lower in the sympathectomized group compared to the control group at 8 and 11 weeks after the nerve injury but not before. Mechanical hypersensitivity tests (pinprick and von Frey hair threshold tests) showed no difference between groups during the study period. Concomitantly, pericellular tyrosine-hydroxylase immunoreactive basket structures were observed around dorsal root ganglia (DRG) neurons 8 weeks after SNI, but were absent at earlier time points after SNI and in sham operated controls. CONCLUSION: These results suggest that the early establishment of neuropathic pain-related behavior after distal nerve injury such as in the SNI model is mechanistically independent of the sympathetic system, whereas the system contributes to the maintenance, albeit after a delay of many weeks, of response to cold-related stimuli

Disentangling the effects of video pace and story realism on children’s attention and response inhibition

This study examined the influence of the realism (realistic vs. unrealistic) and pace (slow vs. fast), in a video of an actor reading a story, on 4-year-old children’s attention and response inhibition. After establishing baseline cognitive performance, 187 children watched novel videos that manipulated realism and pace, while keeping other programme features constant. Irrespective of the pace, watching the videos which presented unrealistic stories improved children’s response inhibition. For attention, there was an interaction between pace and realism. Exposure to the fast-paced video resulted in faster responding, but only when the story was realistic. Together the results suggest that a story’s realism, rather than the video’s pace, affects the inhibitory component of children’s executive function; whereas both pace and realism interact to affect attention. We propose that certain types of feature, embedded in a video, can provide a buffer against the negative effects of exposure to fast pace

Effects of optogenetic stimulation of vasopressinergic retinal afferents on suprachiasmatic neurones

Physiological circadian rhythms are orchestrated by the hypothalamic suprachiasmatic nucleus (SCN). The activity of SCN cells is synchronised by environmental signals, including light information from retinal ganglion cells (RGCs). We recently described a population of vasopressin‐expressing RGCs (VP‐RGC) that send axonal projections to the SCN. To determine how these VP‐RGCs influence the activity of cells in the SCN, we used optogenetic tools to specifically activate their axon terminals within the SCN. Rats were intravitreally injected with a recombinant adeno‐associated virus to express the channelrhodopsin‐2 and the red fluorescent protein mCherry under the vasopressin promoter (VP‐ChR2mCherry). In vitro recordings in acute brain slices showed that approximately 30% of ventrolateral SCN cells responded to optogenetic stimulation with an increase in firing rate that progressively increased during the first 200 seconds of stimulation and which persisted after the end of stimulation. Finally, application of a vasopressin V1A receptor antagonist dampened the response to optogenetic stimulation. Our data suggest that optogenetic stimulation of VP‐RGC axons within the SCN influences the activity of SCN cells in a vasopressin‐dependent manner.The data that support the findings of this study are openly available at http://datashare.is.ed.ac.ukMedical Research Council. Grant Number: MR/M022838http://wileyonlinelibrary.com/journal/jne2020-12-01hj2020Immunolog

Children’s mental health and recreation: Limited evidence for associations with screen use

Aim This study examined the direct and indirect associations between childhood psychopathology symptoms, screen use, media multitasking and participation in non-digital recreation. Methods Psychopathology symptoms, media use, media multitasking, participation in sports, social clubs and reading/games were reported by 520 parents about their 3- to 11-year-old children. The data were analysed using structural equation modelling. Results There were bidirectional negative associations between sports participation and emotional problems (β = −0.16, P < .001 and β = −0.15, P < .001); attention deficit hyperactivity disorder (ADHD) symptoms were associated with reduced reading/games (β = −0.14, P = .004). A bidirectional positive association was found between media use and conduct problems (β = 0.10, P = .015 and β = 0.14, P = .015). Increased media multitasking was indirectly associated with elevated symptoms of ADHD via a reduction in reading/games (β = 0.10, P = .026). However, there was no evidence that screen use mediated the associations between psychopathology symptoms and non-digital recreation. Conclusion Depending on the specific psychological difficulties, children are either less likely to participate in non-digital recreation or are more likely to use screen media or multitask with media. Interventions for children, who experience emotional or behavioural difficulties, are needed to improve participation in non-digital recreation

Leukemia Inhibitory Factor Is an Anti-Inflammatory and Analgesic Cytokine

The mRNA for leukemia inhibitory factor (LIF), a neuroimmune signaling molecule, is elevated during skin inflammation produced by intraplantar injection of complete Freund’s adjuvant (CFA). Moreover, although LIF knock-out mice display normal sensitivity to cutaneous mechanical and thermal stimulation compared with wild-type mice, the degree of CFA-induced inflammation in mice lacking LIF is enhanced in spatial extent, amplitude, cellular infiltrate, and interleukin (IL)-1β and nerve growth factor (NGF) expression. Conversely, local injection of low doses of recombinant LIF diminishes mechanical and thermal hypersensitivity as well as the IL-1β and NGF expression induced by CFA. These data show that upregulation of LIF during peripheral inflammation serves a key, early anti-inflammatory role and that exogenous LIF can reduce inflammatory hyperalgesia

GDNF selectively promotes regeneration of injury-primed sensory neurons in the lesioned spinal cord

Axonal regeneration within the CNS fails due to the growth-inhibitory environment and the limited intrinsic growth capacity of injured neurons. Injury to DRG peripheral axons induces expression of growth associated genes including members of the glial-derived neurotrophic factor (GDNF) signaling pathway and “pre-conditions” the injured cells into an active growth state, enhancing growth of their centrally projecting axons. Here, we show that pre-conditioning DRG neurons prior to culturing increased neurite outgrowth, which was further enhanced by GDNF in a bell-shaped growth response curve. In vivo, GDNF delivered directly to DRG cell bodies facilitated the pre-conditioning effect, further enhancing axonal regeneration beyond spinal cord lesions. Consistent with the in vitro results, the in vivo effect was seen only at low GDNF concentrations. We conclude that peripheral nerve injury upregulates GDNF signaling pathway components and that exogenous GDNF treatment selectively promotes axonal growth of injury-primed sensory neurons in a concentration-dependent fashion