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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.

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.

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.

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 μl) 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 μg/day or 250 μg/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.