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.

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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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Central neuropathic pain (CNP) is an important problem following spinal cord injury (SCI), because it severely affects the quality of life of SCI patients. As in the patient population, the majority of rats develop significant allodynia (CNP rats) after moderate SCI. However, about 10% of SCI rats do not develop allodynia, or develop significantly less allodynia than CNP rats (non-CNP rats). To identify transcriptional changes underlying CNP development after SCI, we used Affymetrix DNA microarrays and RNAs extracted from the spinal cords of CNP and non-CNP rats. DNA microarry analysis showed significantly increased expression of a number of genes associated with inflammation and astrocytic activation in the spinal cords of rats that developed CNP. For example, mRNA levels of glial fibrilary acidic protein (GFAP) and Aquaporin 4 (AQP4) significantly increased in CNP rats. We also found that GFAP, S100b and AQP4 protein elevation persisted for at least 9 months throughout contused spinal cords, consistent with the chronic nature of CNP. Thus, we hypothesize that CNP development results, in part, from dysfunctional, chronically ''over-activated'' astrocytes. Although, it has been shown that activated astrocytes are associated with peripheral neuropathic pain, this has not previously been demonstrated in CNP after SCI.

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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.

Peripheral inflammation induced with a knee joint injection of a mixture of kaolin/carrageenan (k/c) produces primary and secondary hyperalgesia. Inflammatory pain is thought to involve a variety of transmitters released from nerve terminals, including amino acids, substance P (SP) and calcitonin gene-related peptide (CGRP). In the present study, mice deficient in the calcitonin/alpha CGRP gene (CGRP(-/-)) displayed normal responses to noxious stimuli. However, the CGRP knockout mice failed to demonstrate development of secondary hyperalgesia after induction of knee joint inflammation in two tests that assess central sensitization, through testing at sites remote from the primary insult. Nociceptive behavioral responses were assessed using the hot-plate test and paw withdrawal latency (PWL) to radiant heat applied to the hindpaw. The CGRP(-/-) mice showed no signs of secondary hyperalgesia after development of knee joint inflammation, while the expected significant decrease in the PWL was observed in the CGRP(+/+) mice as control. The CGRP(-/-) mice also had a prolonged rather than a shortened response latency in the hot-plate test 4 h after knee joint injection of k/c. Immunohistological study showed that CGRP-like immunoreactivity (CGRP-LI) was absent in the spinal cord and dorsal root ganglia taken from the CGRP(-/-) mice. These results indicate that endogenous CGRP plays an important role in the plastic neurogenic changes occurring in response to peripheral inflammatory events including the development of nociceptive behaviors.