Sigma () receptors, initially described as a subtype of opioid receptors, are now considered unique receptors. Pharmacological studies have distinguished two types of receptors, termed 1 and 2. Of these two subtypes, the 1 receptor has been cloned in humans and rodents, and its amino acid sequence shows no homology with other mammalian proteins. Several psychoactive drugs show high to moderate affinity for 1 receptors, including the antipsychotic haloperidol, the antidepressant drugs fluvoxamine and sertraline, and the psychostimulants cocaine and methamphetamine; in addition, the anticonvulsant drug phenytoin allosterically modulates 1 receptors. Certain neurosteroids are known to interact with 1 receptors, and have been proposed to be their endogenous ligands. These receptors are located in the plasma membrane and in subcellular membranes, particularly in the endoplasmic reticulum, where they play a modulatory role in intracellular Ca2+ signaling. Sigma1 receptors also play a modulatory role in the activity of some ion channels and in several neurotransmitter systems, mainly in glutamatergic neurotransmission. In accordance with their widespread modulatory role, 1 receptor ligands have been proposed to be useful in several therapeutic fields such as amnesic and cognitive deficits, depression and anxiety, schizophrenia, analgesia, and against some effects of drugs of abuse (such as cocaine and methamphetamine). In this review we provide an overview of the present knowledge of 1 receptors, focussing on 1 ligand neuropharmacology and the role of 1 receptors in behavioral animal studies, which have contributed greatly to the potential therapeutic applications of 1 ligands.

Inflammatory pain impacts adversely on the quality of life of patients, often resulting in motor disabilities. Therefore, we studied the effect of peripheral inflammation induced by intraplantar administration of complete Freund's adjuvant (CFA) in mice on a particular form of voluntary locomotion, wheel running, as an index of mobility impairment produced by pain. The distance traveled over 1 hour of free access to activity wheels decreased significantly in response to hind paw inflammation, peaking 24 hours after CFA administration. Recovery of voluntary wheel running by day 3 correlated with the ability to support weight on the inflamed limb. Inflammation-induced mechanical hypersensitivity, measured with von Frey hairs, lasted considerably longer than the impaired voluntary wheel running and is not driving; therefore, the change in voluntary behavior. The CFA-induced decrease in voluntary wheel running was dose-dependently reversed by subcutaneous administration of antiinflammatory and analgesic drugs, including naproxen (10-80 mg/kg), ibuprofen (2.5-20mg/kg), diclofenac (1.25-10mg/kg), celecoxib (2.5-20mg/kg), prednisolone (0.62-5mg/kg), and morphine (0.06-0.5mg/kg), all at much lower doses than reported in most rodent models. Furthermore, the doses that induced recovery in voluntary wheel running did not reduce CFA-induced mechanical allodynia, indicating a greater sensitivity of the former as a surrogate measure of inflammatory pain. We conclude that monitoring changes in voluntary wheel running in mice during peripheral inflammation is a simple, observer-independent objective measure of functional changes produced by inflammation, likely more aligned to the global level of pain than reflexive measures, and much more sensitive to analgesic drug effects.

The somatosensory nervous system is critical for the organism's ability to respond to mechanical, thermal, and nociceptive stimuli. Somatosensory neurons are functionally and anatomically diverse but their molecular profiles are not well-defined. Here, we used transcriptional profiling to analyze the detailed molecular signatures of dorsal root ganglion (DRG) sensory neurons. We used two mouse reporter lines and surface IB4 labeling to purify three major non-overlapping classes of neurons: 1) IB4⁺SNS-Cre/TdTomato⁺, 2) IB4⁻SNS-Cre/TdTomato⁺, and 3) Parv-Cre/TdTomato⁺ cells, encompassing the majority of nociceptive, pruriceptive, and proprioceptive neurons. These neurons displayed distinct expression patterns of ion channels, transcription factors, and GPCRs. Highly parallel qRT-PCR analysis of 334 single neurons selected by membership of the three populations demonstrated further diversity, with unbiased clustering analysis identifying six distinct subgroups. These data significantly increase our knowledge of the molecular identities of known DRG populations and uncover potentially novel subsets, revealing the complexity and diversity of those neurons underlying somatosensation.

Although peripheral nerves can regenerate after injury, proximal nerve injury in humans results in minimal restoration of motor function. One possible explanation for this is that injury-induced axonal growth is too slow. Heat shock protein 27 (Hsp27) is a regeneration-associated protein that accelerates axonal growth in vitro. Here, we have shown that it can also do this in mice after peripheral nerve injury. While rapid motor and sensory recovery occurred in mice after a sciatic nerve crush injury, there was little return of motor function after sciatic nerve transection, because of the delay in motor axons reaching their target. This was not due to a failure of axonal growth, because injured motor axons eventually fully re-extended into muscles and sensory function returned; rather, it resulted from a lack of motor end plate reinnervation. Tg mice expressing high levels of Hsp27 demonstrated enhanced restoration of motor function after nerve transection/resuture by enabling motor synapse reinnervation, but only within 5 weeks of injury. In humans with peripheral nerve injuries, shorter wait times to decompression surgery led to improved functional recovery, and, while a return of sensation occurred in all patients, motor recovery was limited. Thus, absence of motor recovery after nerve damage may result from a failure of synapse reformation after prolonged denervation rather than a failure of axonal growth.