We review many of the recent findings concerning mechanisms and pathways for pain and its modulation, emphasizing sensitization and the modulation of nociceptors and of dorsal horn nociceptive neurons. We describe the organization of several ascending nociceptive pathways, including the spinothalamic, spinomesencephalic, spinoreticular, spinolimbic, spinocervical, and postsynaptic dorsal column pathways in some detail and discuss nociceptive processing in the thalamus and cerebral cortex. Structures involved in the descending analgesia systems, including the periaqueductal gray, locus ceruleus, and parabrachial area, nucleus raphe magnus, reticular formation, anterior pretectal nucleus, thalamus and cerebral cortex, and several components of the limbic system are described and the pathways and neurotransmitters utilized are mentioned. Finally, we speculate on possible fruitful lines of research that might lead to improvements in therapy for pain.

Background Current arthritis treatments often have side-effects attributable to active compounds as well as route of administration. Cannabidiol (CBD) attenuates inflammation and pain without side-effects, but CBD is hydrophobic and has poor oral bioavailability. Topical drug application avoids gastrointestinal administration, first pass metabolism, providing more constant plasma levels. Methods This study examined efficacy of transdermal CBD for reduction in inflammation and pain, assessing any adverse effects in a rat complete Freund’s adjuvant-induced monoarthritic knee joint model. CBD gels (0.6, 3.1, 6.2 or 62.3 mg/day) were applied for 4 consecutive days after arthritis induction. Joint circumference and immune cell invasion in histological sections were measured to indicate level of inflammation. Paw withdrawal latency (PWL) in response to noxious heat stimulation determined nociceptive sensitization, and exploratory behaviour ascertained animal’s activity level. Results Measurement of plasma CBD concentration provided by transdermal absorption revealed linearity with 0.6–6.2 mg/day doses. Transdermal CBD gel significantly reduced joint swelling, limb posture scores as a rating of spontaneous pain, immune cell infiltration and thickening of the synovial membrane in a dose-dependent manner. PWL recovered to near baseline level. Immunohistochemical analysis of spinal cord (CGRP, OX42) and dorsal root ganglia (TNFα) revealed dose-dependent reductions of pro-inflammatory biomarkers. Results showed 6.2 and 62 mg/day were effective doses. Exploratory behaviour was not altered by CBD indicating limited effect on higher brain function. Conclusions These data indicate that topical CBD application has therapeutic potential for relief of arthritis pain-related behaviours and inflammation without evident side-effects.

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The descending projections of the periaqueductal gray (PAG) have been studied in the rat using the anterograde tracer Phaseolus vulgaris-leucoagglutinin. The tracer was injected into the dorsolateral or ventrolateral subdivisions of the PAG at rostral or caudal sites. It was found that the patterns of the descending projections of the rostral and caudal parts of the dorsolateral PAG were the same and that the patterns of the descending projections of the rostral and caudal parts of the ventrolateral PAG were the same. However, the patterns of projections of the dorsolateral and ventrolateral PAG subregions were substantially different. These results suggest that the dorsolateral and ventrolateral parts of the PAG are organized into longitudinal columns that extend throughout the length of the PAG. The axons of PAG neurons descended through the pons and medulla via two routes. A small fiber bundle was present in the periaqueductal gray and in the periventricular area. This bundle distributed fibers and terminals locally within the periaqueductal gray and in the locus coeruleus and Barrington's nucleus. A larger bundle had a diffuse arrangement in the pontine reticular formation, however, and it had a more restricted distribution in the medulla, where it occupied a position dorsolateral to the pyramid. This bundle supplied structures in the pontine and medullary tegmentum. The dorsolateral column preferentially supplied the locus coeruleus, subcoeruleus, the gigantocellular nucleus pars alpha, the rostral part of the paragigantocellular nucleus, and the region of the A5 noradrenergic cell group. The ventrolateral column preferentially supplied the nucleus raphe magnus, the caudal part of the lateral paragigantocellular nucleus, and the rostroventrolateral reticular nucleus.