Pain perception: Is there a role for primary somatosensory cortex?

Anatomical, physiological, and lesion data implicate multiple cortical regions in the complex experience of pain. These regions include primary and secondary somatosensory cortices, anterior cingulate cortex, insular cortex, and regions of the frontal cortex. Nevertheless, the role of different cortical areas in pain processing is controversial, particularly that of primary somatosensory cortex (S1). Human brain-imaging studies do not consistently reveal pain-related activation of S1, and older studies of cortical lesions and cortical stimulation in humans did not uncover a clear role of S1 in the pain experience. Whereas studies from a number of laboratories show that S1 is activated during the presentation of noxious stimuli as well as in association with some pathological pain states, others do not report such activation. Several factors may contribute to the different results among studies. First, we have evidence demonstrating that S1 activation is highly modulated by cognitive factors that alter pain perception, including attention and previous experience. Second, the precise somatotopic organization of S1 may lead to small focal activations, which are degraded by sulcal anatomical variability when averaging data across subjects. Third, the probable mixed excitatory and inhibitory effects of nociceptive input to S1 could be disparately represented in different experimental paradigms. Finally, statistical considerations are important in interpreting negative findings in S1. We conclude that, when these factors are taken into account, the bulk of the evidence now strongly supports a prominent and highly modulated role for S1 cortex in the sensory aspects of pain, including localization and discrimination of pain intensity.

The genetic mediation of individual differences in sensitivity to pain and its inhibition

The underlying bases of the considerable interindividual variability in pain-related traits are starting to be revealed. Although the relative importance of genes versus experience in human pain perception remains unclear, rodent populations display large and heritable differences in both nociceptive and analgesic sensitivity. The identification and characterization of particularly divergent populations provides a powerful initial step in the genetic analysis of pain, because these models can be exploited to identify genes contributing to the behavior-level variability. Ultimately, DNA sequence differences representing the differential alleles at pain-relevant genes can be identified. Thus, by using a combination of “top-down” and “bottom-up” strategies, we are now able to genetically dissect even complex biological traits like pain. The present review summarizes the current progress toward these ends in both humans and rodents.

kappa-Opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system.

Using the mouse delta-opioid receptor cDNA as a probe, we have isolated genomic clones encoding the human mu- and kappa-opioid receptor genes. Their organization appears similar to that of the human delta receptor gene, with exon-intron boundaries located after putative transmembrane domains 1 and 4. The kappa gene was mapped at position q11-12 in human chromosome 8. A full-length cDNA encoding the human kappa-opioid receptor has been isolated. The cloned receptor expressed in COS cells presents a typical kappa 1 pharmacological profile and is negatively coupled to adenylate cyclase. The expression of kappa-opioid receptor mRNA in human brain, as estimated by reverse transcription-polymerase chain reaction, is consistent with the involvement of kappa-opioid receptors in pain perception, neuroendocrine physiology, affective behavior, and cognition. In situ hybridization studies performed on human fetal spinal cord demonstrate the presence of the transcript specifically in lamina II of the dorsal horn. Some divergences in structural, pharmacological, and anatomical properties are noted between the cloned human and rodent receptors.