Coding of facial expressions of pain in the laboratory mouse.

Facial expression is widely used as a measure of pain in infants; whether nonhuman animals display such pain expressions has never been systematically assessed. We developed the mouse grimace scale (MGS), a standardized behavioral coding system with high accuracy and reliability; assays involving noxious stimuli of moderate duration are accompanied by facial expressions of pain. This measure of spontaneously emitted pain may provide insight into the subjective pain experience of mice.

Shifting the sociometer: opioid receptor blockade lowers self-esteem.

Given the evolutionary importance of social ties for survival, humans are thought to have evolved psychobiological mechanisms to monitor and safeguard the status of their social bonds. At the psychological level, self-esteem is proposed to function as a gauge-'sociometer'-reflecting one's social belongingness status. At the biological level, endogenous opioids appear to be an important substrate for the hedonic signalling needed to regulate social behaviour. We investigated whether endogenous opioids may serve as the biological correlate of the sociometer. We administered 50 mg naltrexone (an opioid receptor antagonist) and placebo in a counterbalanced order to 26 male and female participants on two occasions ∼1 week apart. Participants reported lower levels of self-esteem-particularly self-liking-on the naltrexone (vs placebo) day. We also explored a potential behavioural consequence of naltrexone administration: attentional bias to accepting (smiling) faces-an early-stage perceptual process thought to maximize opportunities to restore social connection. Participants exhibited heightened attentional bias towards accepting faces on the naltrexone (vs placebo) day, which we interpret as an indicator of heightened social need under opioid receptor blockade. We discuss implications of these findings for understanding the neurobiological underpinnings of sociality as well as the relationship between adverse social conditions, low self-esteem and psychopathology.

Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice.

The innate immune system is increasingly appreciated to play an important role in the mediation of chronic pain, and one molecule implicated in this process is the Toll-like receptor 4 (TLR4). Here, using pharmacological and genetic manipulations, we found that activating TLR4 in the spinal cord, with the agonist lipopolysaccharide (LPS), causes robust mechanical allodynia but only in male mice. Spinal LPS had no pain-producing effect in female mice. TLR4 also has a sex-specific role in inflammatory (complete Freund's adjuvant) and neuropathic (spared nerve injury) pain: pain behaviors were TLR4 dependent in males but TLR4 independent in females. The sex differences appear to be specific to the spinal cord, as LPS administered to the brain or the hindpaw produces equivalent allodynia in both sexes, and specific to pain, as intrathecal LPS produces equivalent hypothermia in both sexes. The involvement of TLR4 in pain behaviors in male mice is dependent on testosterone, as shown by gonadectomy and hormone replacement. We found no sex differences in spinal Tlr4 gene expression at baseline or after LPS, suggesting the existence of parallel spinal pain-processing circuitry in female mice not involving TLR4.

Anhedonia to music and mu-opioids: Evidence from the administration of naltrexone.

Music's universality and its ability to deeply affect emotions suggest an evolutionary origin. Previous investigators have found that naltrexone (NTX), a µ-opioid antagonist, may induce reversible anhedonia, attenuating both positive and negative emotions. The neurochemical basis of musical experience is not well-understood, and the NTX-induced anhedonia hypothesis has not been tested with music. Accordingly, we administered NTX or placebo on two different days in a double-blind crossover study, and assessed participants' responses to music using both psychophysiological (objective) and behavioral (subjective) measures. We found that both positive and negative emotions were attenuated. We conclude that endogenous opioids are critical to experiencing both positive and negative emotions in music, and that music uses the same reward pathways as food, drug and sexual pleasure. Our findings add to the growing body of evidence for the evolutionary biological substrates of music.

The neurochemistry of music.

Music is used to regulate mood and arousal in everyday life and to promote physical and psychological health and well-being in clinical settings. However, scientific inquiry into the neurochemical effects of music is still in its infancy. In this review, we evaluate the evidence that music improves health and well-being through the engagement of neurochemical systems for (i) reward, motivation, and pleasure; (ii) stress and arousal; (iii) immunity; and (iv) social affiliation. We discuss the limitations of these studies and outline novel approaches for integration of conceptual and technological advances from the fields of music cognition and social neuroscience into studies of the neurochemistry of music.

Behavioral evidence for photophobia and stress-related ipsilateral head pain in transgenic Cacna1a mutant mice.

Migraine is a highly prevalent, disabling and complex episodic brain disorder whose pathogenesis is poorly understood, due in part to the lack of valid animal models. Here we report behavioral evidence of hallmark migraine features, photophobia and unilateral head pain, in transgenic knock-in mice bearing human familial hemiplegic migraine, type 1 (FHM-1) gain-of-function missense mutations (R192Q or S218L) in the Cacna1a gene encoding the CaV2.1 calcium channel α1 subunit. Photophobia was demonstrated using a modified elevated plus maze in which the safe closed arms were brightly illuminated; mutant mice avoided the light despite showing no differences in the standard (anxiety) version of the test. Multiple behavioral measures suggestive of spontaneous head pain were found in 192Q mutants subjected to novelty and/or restraint stress. These behaviors were: (1) more frequent in mutant versus wildtype mice; (2) lateralized in mutant but not in wildtype mice; (3) more frequent in females versus males; and (4) dose-dependently normalized by systemic administration of 2 different acute analgesics, rizatriptan and morphine. Furthermore, some of these behaviors were found to be more frequent and severe in 218L compared to 192Q mutants, consistent with the clinical presentation in humans. We suggest that Cacna1a transgenic mice can experience migraine-related head pain and can thus serve as unique tools to study the pathogenesis of migraine and test novel antimigraine agents.

Pain characteristic differences between subacute and chronic back pain.

UNLABELLED: Back pain is commonly classified based on duration. There is currently limited information regarding differences in the clinical features of back pain between these duration-based groupings. Here, we compared the pain characteristics of patients with subacute (SBP; pain 6-16 weeks, n = 40) and chronic back pain (CBP; pain ≥1 year, n = 37) recruited from the general population. CBP patients reported significantly higher pain intensity on the Visual Analogue Scale (VAS) compared to SBP patients. Based on this finding, we investigated group differences and their dependence on VAS for the Beck Depression Inventory (BDI), sensory and affective dimensions of the McGill Pain Questionnaire (MPQ-S and MPQ-A), Neuropathic Pain Scale (NPS), and the variability of spontaneous pain. Correction for VAS abolished significant group differences on the MPQ-S, MPQ-A and NPS. Only a significant difference in the variability of spontaneous pain was independent of VAS. Finally, whereas SBP patients displayed a higher incidence of unilateral pain radiating down the legs/buttocks, there was a shift towards more bilateral pain in CBP patients. In summary, SBP and CBP groups differ on 3 independent parameters: VAS ratings, pain location, and temporal dynamics of spontaneous pain. PERSPECTIVE: The present study reports differences in the characteristics of back pain between duration-based groupings in the general population. The main outcome of the study is the demonstration that a small number of descriptors are required to characterize the difference between SBP and CBP.

Sex differences in the effects of amiloride on formalin test nociception in mice.

Amiloride is a nonspecific blocker of acid-sensing ion channels (ASICs) that have been recently implicated in the mediation of mechanical and chemical/inflammatory nociception. Preliminary data using a transgenic model are suggestive of sex differences in the role of ASICs. We report here that systemic administration of amiloride (10-70 mg/kg ip) produces a robust, dose-dependent blockade of late/tonic phase nociceptive behavior on the mouse formalin test (5%; 20 microl) in female but not male mice, completely abolishing the known sex difference in formalin test response. Adult gonadectomy produced a "switching" of sex differences in amiloride efficacy, with castrated males displaying an amiloride blockade and ovariectomized females rendered less sensitive to amiloride. Gonadectomized mice could be switched back to their intact status using chronic estrogen benzoate or testosterone propionate replacement via osmotic minipump (6 microg/day or 250 microg/day, respectively). It is unclear whether this striking sex difference is due to sex-specific involvement of ASICs in pain processing, but the present data represent one of the first demonstrations of pain-related sex differences with no obvious opioid involvement.

Social modulation of pain as evidence for empathy in mice.

Empathy is thought to be unique to higher primates, possibly to humans alone. We report the modulation of pain sensitivity in mice produced solely by exposure to their cagemates, but not to strangers, in pain. Mice tested in dyads and given an identical noxious stimulus displayed increased pain behaviors with statistically greater co-occurrence, effects dependent on visual observation. When familiar mice were given noxious stimuli of different intensities, their pain behavior was influenced by their neighbor's status bidirectionally. Finally, observation of a cagemate in pain altered pain sensitivity of an entirely different modality, suggesting that nociceptive mechanisms in general are sensitized.