SUMMARY Primary afferents are known to be inhibited by kappa opioid receptor (KOR) signaling. However, the specific types of somatosensory neurons that express KOR remain unclear. Here, using a newly developed KOR-cre knockin allele, viral tracing, single-cell RT-PCR, and ex vivo recordings, we show that KOR is expressed in several populations of primary afferents: a subset of peptidergic sensory neurons, as well as low-threshold mechanoreceptors that form lanceolate or circumferential endings around hair follicles. We find that KOR acts centrally to inhibit excitatory neurotransmission from KOR-cre afferents in laminae I and III, and this effect is likely due to KOR-mediated inhibition of Ca2+ influx, which we observed in sensory neurons from both mouse and human. In the periphery, KOR signaling inhibits neurogenic inflammation, nociceptor sensitization by inflammatory mediators, and pain and itch behaviors. These experiments provide a rationale for the therapeutic use of peripherally restricted KOR agonists.

Rationale Women represent a vulnerable and growing population with respect to alcohol abuse. Elevated glucocorticoid exposure in adolescence increases addiction risk and stress sensitivity in adulthood. However, little is known about sex differences in ethanol craving-like behavior. Objective This study characterized sex differences in ethanol-motivated behavior following ethanol-paired cues and/or acute stimulation of the HPA axis in male and female rats with or without exposure to chronically elevated glucocorticoids in adolescence. Methods Adolescent corticosterone-treated (Experiment 1) or naïve (Experiment 2) male and female rats were trained as adults to self-administer ethanol paired with a cue, and tested for the effects of this cue, alone or in combination with yohimbine, on the reinstatement of ethanol seeking. Results Females showed elevated ethanol self-administration and seeking compared to males. In Experiment 1, corticosterone exposure in adolescence augmented cue-induced reinstatement of ethanol seeking in females only, and females were more sensitive to yohimbine in promoting reinstatement. Experiment 2 replicated these findings and showed that exposure to both yohimbine and alcohol-related cues enhanced the reinstatement of alcohol seeking, producing additive effects in females. Corticosterone levels were higher in females and in yohimbine-treated rats, and corticosterone and estradiol correlated with responding during reinstatement. Conclusions Chronic manipulations in adolescence and acute manipulations in adulthood of the HPA axis increase cue-induced reinstatement of ethanol seeking to a greater degree in females than in males. Elucidating the mechanisms that underlie these effects may lead to the development of sex-specific interventions aimed at mitigating alcohol relapse risk in females.

Use of marijuana (Cannabis sativa) often begins in adolescence, and heavy adolescent marijuana use is often associated with impaired cognitive function in adulthood. However, clinical reports of long-lasting cognitive deficits, particularly in subjects who discontinue use in adulthood, are mixed. Moreover, dissociating innate differences in cognitive function from cannabis-induced deficits is challenging. Therefore, the current study sought to develop a rodent model of adolescent cannabinoid self-administration (SA), using the synthetic cannabinoid receptor agonist WIN55,212-2 (WIN), in order to assess measures of relapse/reinstatement of drug seeking and long-term effects on cognitive function assessed in a delay-match-to-sample working memory task and a spatial recognition task. Adolescent male rats readily self-administered WIN in 2-h or 6-h sessions/day, but did not demonstrate an escalation of intake with 6-h access. Rats exhibited significant cue-induced reinstatement of WIN seeking that increased with 21 days of abstinence (ie, 'incubation of craving'). Cognitive testing occurred in adulthood under drug-free conditions. Both 2-h and 6-h adolescent WIN SA groups exhibited significantly better working memory performance in adulthood relative to sucrose SA controls, and performance was associated with altered expression of proteins regulating GABAergic and glutamatergic signaling in the prefrontal cortex. Self-administered WIN did not produce either acute or chronic effects on short-term memory, but experimenter administration of WIN in adolescence, at doses previously reported in the literature, produced acute deficits in short-term memory that recovered with abstinence. Thus, SA of a rewarding cannabinoid in adolescence does not produce long-term cognitive dysfunction.

Preclinical evidence has highlighted the importance of the μ-opioid peptide (MOP) receptor on primary afferents for both the analgesic actions of MOP receptor agonists, as well as the development of tolerance, if not opioid-induced hyperalgesia. There is also growing interest in targeting other opioid peptide receptor subtypes (δ-opioid peptide [DOP], κ-opioid peptide [KOP], and nociceptin/orphanin-FQ opioid peptide [NOP]) on primary afferents, as alternatives to MOP receptors, which may not be associated with as many deleterious side effects. Nevertheless, results from several recent studies of human sensory neurons indicate that although there are many similarities between rodent and human sensory neurons, there may also be important differences. Thus, the purpose of this study was to assess the distribution of opioid receptor subtypes among human sensory neurons. A combination of pharmacology, patch-clamp electrophysiology, Ca2+ imaging, and single-cell semiquantitative polymerase chain reaction was used. Our results suggest that functional MOP-like receptors are present in approximately 50% of human dorsal root ganglion neurons. δ-opioid peptide-like receptors were detected in a subpopulation largely overlapping that with MOP-like receptors. Furthermore, KOP-like and NOP-like receptors are detected in a large proportion (44% and 40%, respectively) of human dorsal root ganglion neurons with KOP receptors also overlapping with MOP receptors at a high rate (83%). Our data confirm that all 4 opioid receptor subtypes are present and functional in human sensory neurons, where the overlap of DOP, KOP, and NOP receptors with MOP receptors suggests that activation of these other opioid receptor subtypes may also have analgesic efficacy.

Different peripheral nerve injuries cause neuropathic pain through distinct mechanisms. Even the site of injury may impact underlying mechanisms, as indicated by the clinical finding that the antiseizure drug carbamazepine (CBZ) relieves pain because of compression injuries of trigeminal but not somatic nerves. We leveraged this observation in the present study hypothesizing that because CBZ blocks voltage-gated sodium channels (VGSCs), its therapeutic selectivity reflects differences between trigeminal and somatic nerves with respect to injury-induced changes in VGSCs. CBZ diminished ongoing and evoked pain behavior in rats with chronic constriction injury (CCI) to the infraorbital nerve (ION) but had minimal effect in rats with sciatic nerve CCI. This difference in behavior was associated with a selective increase in the potency of CBZ-induced inhibition of compound action potentials in the ION, an effect mirrored in human trigeminal versus somatic nerves. The increase in potency was associated with a selective increase in the efficacy of the NaV1.1 channel blocker ICA-121431 and NaV1.1 protein in the ION, but no change in NaV1.1 mRNA in trigeminal ganglia. Importantly, local ICA-121431 administration reversed ION CCI-induced hypersensitivity. Our results suggest a novel therapeutic target for the treatment of trigeminal neuropathic pain.SIGNIFICANCE STATEMENTThis study is based on evidence of differences in pain and its treatment depending on whether the pain is above (trigeminal) or below (somatic) the neck, as well as evidence that voltage-gated sodium channels (VGSCs) may contribute to these differences. The focus of the present study was on channels underlying action potential propagation in peripheral nerves. There were differences between somatic and trigeminal nerves in VGSC subtypes underlying action potential propagation both in the absence and presence of injury. Importantly, because the local block of NaV1.1 in the trigeminal nerve reverses nerve injury-induced mechanical hypersensitivity, the selective upregulation of NaV1.1 in trigeminal nerves suggests a novel therapeutic target for the treatment of pain associated with trigeminal nerve injury.