Descending control of pain

-flight/ fight response>> increase HR/ BP

-animal retracts from pain- withdrawal etc

Background- Hyperalgesia is one of the debilitating complications of diabetes. This condition might be caused by defects in central or peripheral processing of pain signals. In the present study we aim to see if diabetic hyperalgesia is related to changes in Transient Receptor Potential Vanilloid 1 (TRPV1) or Cannabinoid CB1 receptors of periaqueductal gray (PAG). Activation of glutamatergic projecting neurons in midbrain ventrolateral periaqueductal gray (VL-PAG) induces antinociception. Agonists of TRPV1 in VL-PAG increase firing of these glutamatergic neurons. CB1 receptor agonists also cause antinociception by decreasing Gamma Aminobutyric Acid (GABA) release in PAG and disinhibiting these glutamatergic neurons. Methods- antinociceptive effect of intra VL-PAG microinjections of CB1 and TRPV1 agonists [WIN55,212-2 (WIN) and capsaicin respectively] were compared in diabetic vs. non-diabetic rats, meanwhile mRNA expression of these receptors in PAG of diabetic and non-diabetic rats were evaluated by real time polymerase chain reaction (real time PCR) assay. Results- Our results showed a decrease of capsaicin antinociceptive effect (P < 0.05) and TRPV1 receptor expression (P = 0.023) but an increase in WIN antinociceptive effect (P < 0.05) and CB1 receptor expression (P < 0.001) in PAG of diabetic vs. non-diabetic rats. Conclusion-down-regulation of TRPV1 receptors in PAG is responsible for reduced antinociceptive effect of TRPV1 agonist. This finding may be an underlying cause of diabetic hyperalgesia. Up-regulation of CB1 receptors might be a compensatory mechanism but the precise elucidation of the effects of CB1 changes on disinhibition needs further studies.

Nahman-Averbucha et al (2013) Background and purpose Conditioned pain modulation (CPM) is a testing paradigm representing features of diffuse noxious inhibitory control. There is large diversity in the paradigms applied to induce CPM, and the consistency in CPM responses assessed by different paradigms is largely unknown. We aimed to characterize and explore the associations between the CPM responses assessed by different paradigms in the same cohort. Methods Thirty-three healthy middle-aged subjects underwent six CPM paradigms. The ‘test-stimuli’, consisted of thermal and mechanical modalities, using pain thresholds, suprathreshold pain and temporal summation types of measurements. The ‘conditioning-stimulus’ consisted of a contact heat stimulus applied to the thener of the left hand for 60 s at an intensity of 46.5 °C. Results Large variability was observed among the responses to the different CPM paradigms. Surprisingly, no correlations were found between the various CPM responses. Conclusions The variability in the CPM responses may suggest that the capacity of pain modulation is a multifaceted trait, whose expression varies with the application of different CPM paradigms. Implications Considering that CPM responses may represent different processes when assessed by different paradigms, we encourage the use of more than one CPM paradigm.

Fig. 1. Schematic illustrates main topics of this review: midline PAG-RVM system, which exerts bidirectional control over dorsal horn nociceptive processing, and the DRt and VLM in the caudal medulla. DRt is thought to be facilitating, and VLM primarily inhibitory, although it may, like the RVM, have both an inhibitory and facilitatory influence. The PAG especially, but also the RVM, DRt and VLM (not shown) receive important direct and indirect inputs from limbic forebrain areas including anterior cingulate cortex (ACC), amygdala (AMY), dorsomedial nucleus of the hypothalamus (DMH), and medial prefrontal cortex (MPC).

descending control of spinal nociception-overview

PAG-RVM medulla-spinal axis

functional organisation of the PAG

Mohammadi-Farani et al (2010)

Conditioned pain modulation (CPM)