Descending control of Pain

Annotations:

• Inhibitory control from the PAG-RVM system preferentially suppresses nociceptive inputs mediated by C-fibers, preserving sensory-discriminative information conveyed by more rapidly conducting A-fibers

1. RVM medulla-spinal

   Annotations:

   • rostal ventromedial medulla- spinal cord axis- descending pathway for controlling pain in the spinal cord via the PAG
   • the neural basis for bidirectional control from the midline system is two populations of neurons, ON-cells and OFF-cells, that are differentially recruited by higher structures important in fear, illness and psychological stress to enhance or inhibit pain

   Attachments:

   • Descending control of pain
   1. ON/OFF/ neutral cells

      Annotations:

      • Fields et al., 1983  showed that RVM neurons exhibited abrupt state changes; ON-cells and OFF-cells (The remaining neurons were classified by exclusion, and referred to as NEUTRAL-cells.)  
      1. OFF-cells

         Annotations:

         • function as the antinociceptive output - Heinricher labs showed by various pharmacological profiles/ experiments
         1. inhibitory
      2. ON-cells
         1. Facilitatory role
            1. correlation studies

               Annotations:

               • variety of conditions in which behavioral hyperalgesia was correlated with increased activity of ON-cells and suppression of OFF-cell firing (Barbaro et al., 1986, Bederson et al., 1990, Fields et al., 1983b, Heinricher et al., 1989, McGaraughty et al., 2003, Morgan and Fields, 1994, Morgan et al., 1994 and Pan et al., 2000).  
            2. combined single-cell recording/microinjection

               Annotations:

               •   o   (stronger approach is to determine the net behavioral effect (facilitatory or inhibitory) of targeted activation or inactivation of each population )- neuronal activity within the RVM and nocifensor reflex threshold are recorded before, during and after focal application of a drug within the RVM was developed (Heinricher and Tortorici, 1994). o   >> many studies using this approach found that ON-cells are the facilitating output of the RVM   
         2. conflicting evidence

            Annotations:

            •    o   reports that noxious-evoked activation of apparent ON-cells is correlated with analgesia rather than hyperalgesia (Azami et al., 2001, Li et al., 1998 and Thurston and Randich, 1995), and claims that ON- and OFF-cells had no role in pain modulation (Mason, 2001), underscored the limitations of correlative methods for defining the function of these neurons.   
         3. hyperagesia and PGE2

            Annotations:

            • Prostaglandin E2 (PGE2) in the medial preoptic area similarly activates ON-cells and produces hyperalgesia (Heinricher et al., 2004). 
      3. NEUTRAL
         1. unknown
            1. serotonin
      4. positive feedback loop
   2. Functions
      1. required for hyperalgesia/ allodynia
      2. stress/ illness

         Annotations:

         • organizing strategies for coping with intrinsic and extrinsic stressors
         1. Fear- amygdala

            Annotations:

            • The amygdala is known to be a critical relay to the PAG-RVM system in the analgesic states associated with intense fear (Helmstetter, 1992 and Helmstetter and Tershner, 1994), and opioid action in the basolateral nucleus of the amygdala recruits OFF-cells in the RVM (McGaraughty and Heinricher, 2002). 
         2. Sickness

            Annotations:

            • Prostaglandin E2 (PGE2) in the medial preoptic area similarly activates ON-cells and produces hyperalgesia (Heinricher et al., 2004). This is of interest because the medial preoptic area is a primary site at which PGE2 acts to organize autonomic, neuroendocrine and behavioral elements of the sickness response (Elmquist et al., 1997, Ivanov and Romanovsky, 2004 and Kluger, 1991). 
         3. stress and hypothalamus

            Annotations:

            • Activation of the dorsomedial nucleus of the hypothalamus, a region implicated in autonomic aspects of the response to psychological stress, also evokes behavioral hyperalgesia mediated by ON-cells (Martenson et al., in press). 
      3. central site of analgesia

         Annotations:

         • central site of action of analgesic agents including opioids, cyclooxygenase inhibitors, and cannabinoids 
   3. positive feedback loop
   4. Conflicting descending control

      Annotations:

      • The output can sometimes be facilitatory or inhibitory depending on various factors
      1. Drugs
         1. Opiods

            Annotations:

            • Focal application of opioids >> in the RVM evokes analgesia Heinricher and Morgan, 1999, Heinricher and Neubert, 2004 and Kovelowski et al., 2000
         2. neuropeptide cholecystokinin

            Annotations:

            •    o   Whether neurotensin microinjection in the RVM produces analgesia or hyperalgesia varies with dose, and presumably, the receptor type activated (Buhler et al., 2005, Neubert et al., 2004, Smith et al., 1997 and Urban and Smith, 1994).   
            • neuropeptide cholecystokinin produces behavioral hyperalgesia 
      2. lesions

         Annotations:

         •    o  Lesion or general inactivation of RVM neurons may produce modest hyperalgesia or have no effect under basal conditions, but raise the nociceptive threshold in acute and chronic hyperalgesic states (Heinricher and Kaplan, 1991, Kaplan and Fields, 1991 and Porreca et al., 2002).   
      3. electrical stimulation

         Annotations:

         •    o   Electrical stimulation >>can  produce facilitation or inhibition with different thresholds, or over the course of a developing inflammatory response (Ren and Dubner, 2002, Zhuo and Gebhart, 1990, Zhuo and Gebhart, 1992 and Zhuo and Gebhart, 1997).   
      4. How>>
2. PAG

   Annotations:

   • central site of action of endogenous and exogenous pain- modulatory substances
   1. organisation

      Attachments:

      • Descending control of pain
   2. techniques
      1. stimulating electrodes
         1. PAG-only
         2. PAG + heating

            Annotations:

            • shows whether PAG modulates C-fibre/ A-fibre evoked responses
            1. Yeomans et al. (1996)
         3. PAG + Fos + heating
         4. (-) chemical vs electrical stimulation

            Annotations:

            • see above
      2. recording electrodes
      3. behavioural responses
      4. expression of proteins
         1. Fos

            Annotations:

            • c-fos detection as a functional anatomical method point to dynamic changes in acute and chronic pain
      5. Effects of drugs
         1. analgesics
      6. Conditioned pain modulation (CPM)

         Annotations:

         • Nahman-Averbucha et al (2013)

         Attachments:

         • Descending control of pain
   3. Evidence
      1. stimulation of PAG
         1. Class 2 neurons

            Annotations:

            • wide-dynamic range (WDR)- respond to nociceptive and innocuous stimuli
            1. DL/L PAG
               1. McMullan and Lumb, 2006

                  Annotations:

                  • the sensori-discriminative information conveyed in A-fibre nociceptors is maintained and that the information from C-nociceptors is lost in the presence of descending control from the DL/L-PAG.

                  Attachments:

                  • Descending control of pain 2
            2. VL-PAG
               1. Waters and Lumb, 2008

                  Attachments:

                  • Descending control of pain 2
            3. slow/ fast skin heating

               Annotations:

               • tests the effects of activating C- and A- nociceptors and the modulation by PAG
         2. C-/A- nociceptors
            1. mechanisms of descending control

               Annotations:

               • Mechanisms of differential descending control of C- versus A-fiber-evoked spinal nociception

               Attachments:

               • Descending control of pain 2
               1. Functional significance

                  Annotations:

                  • These findings may also be relevant to development and maintenance of chronic pain states, since C-fiber inputs play a significant role in the sensitization of dorsal horn neurons (Fuchs et al., 2000 and Magerl et al., 2001). Descending inhibitory control of those inputs may in many cases limit development of a central sensitized state, and failure of this inhibition may permit recruitment of descending facilitation 
                  1. distracting C-fibre inputs are supressed
                  2. rapidly conducted A-fibre inputs are enhaced
               2. superficial dorsal horn
                  1. C-fibre inputs
                  2. A-fibre inputs
                  3. Descending control mainly terminates here
               3. Deep dorsal horn

                  Annotations:

                  • secondary to the superficial dorsal horn
                  1. indirect/ direct C-/A-fibre inputs

                     Annotations:

                     • indirect via superficial interneurons
                  2. some descending control
               4. strong C+ve

                  Annotations:

                  • “strong” C+ve neurons in the deep dorsal horn receive C-fiber input relayed by numerous superficial C-receptive neurons
               5. weak C-ve

                  Annotations:

                  • “weak” C+ve neurons are targeted by relatively few C-receptive interneurons
               6. C-ve

                  Annotations:

                  • C−ve neurons in the deep dorsal horn receive no projections from superficial C-receptive interneurons
                  1. reciprocal inhibition, disinihibition by descending control

                     Annotations:

                     • Evidence- Waters and Lumb, 2008- Following PAG stimulation pinch-evoked responses of class 2 neurons with C-fibre inputs were depressed, whereas those without C-fibre inputs were enhanced (probably A-mediated)Further experiments indicated these facilitatory effects were at least partly due to a reduction in C-fibre-mediated segmental inhibition.
                     • evidence has been provided for reciprocal segmental inhibition of deep dorsal horn neurons, whereby activity in C+ve neurons inhibits activity in C−ve neurons and vice versa (Waters and Lumb, 2008). Descending inhibition of C+ve neurons will thus disinhibit weak C+ve and C−ve neurons

                     Attachments:

                     • Descending control of pain 2
               7. net facilitatory effect
            2. Jurna, 1980 etc

               Annotations:

               • studies like this one compared the descending control of A- versus C-nociceptor-evoked responses in the spinal dorsal horn methods- electrical stimulation of peripheral nerves
               1. (-) non-selective C+ve/ C-ve

                  Annotations:

                  • Electrical stimulation of peripheral nerves evokes un-physiological, synchronous inputs to the spinal cord, which may be resistant to modulation. It also simultaneously activates afferents innervating excitatory and inhibitory receptive fields of spinal neurons i.e. both C+ve and C-ve afferents
                  • One approach to overcoming these limitations is to establish the profile of A- and C-fiber input to an individual neuron using electrical stimulation, which enables assumptions about the fiber types mediating the naturally evoked responses of that cell
                  1. (+) C+/C- neurons

                     Annotations:

                     • establishing a profile in which neurons are either C+ve (those showing a response at C-fiber latency, in addition to A-fiber responses- mediated by C-fibres) or C-ve ( those in which there is no evidence of C-fiber-evoked activity- mediated by A-fibres)
                     1. Waters and Lumb, 2008

                        Annotations:

                        • Following activation of PAG -evoked responses of C+ve cells are generally depressed, whilst those of C−ve cells show a net facilitation >> indicating that descending control from the PAG distinguishes between neurons with and without C-fiber inputs  
                     2. (-) C+= C-fibre/ C-= Afibre??

                        Annotations:

                        • A limitation of the approach described above is that it relies on the assumption that pinch-evoked responses of C+ve are mediated by C- and/or A-fiber nociceptors, and C−ve neurons solely by A-fibers. It would be desirable to identify a more direct approach in which A- or C-fiber nociceptors were activated differentially using natural stimulation of the cutaneous receptive field.
                        1. (+) skin heating

                           Annotations:

                           • use different rates of skin heating to preferentially activate A- or C-heat nociceptors, as first described by Yeomans et al. (1996) 
                           •    This technique has been further refined and, in a number of experimental paradigms, has been shown reliably to activate these distinct groups of nociceptors (Leith et al., 2007 and McMullan et al., 2004). Fast rates of heating (7.5 ± 1 °C s− 1) are used to preferentially activate A-fiber (myelinated, capsaicin-insensitive) heat nociceptors, whereas slow rates of heating (2.5 ± 1 °C s− 1) activate C-fiber (unmyelinated, capsaicin-sensitive) heat nociceptors. 
                           1. Fast rate= A-fibres
                           2. Slow rate= C-fibres
                           3. PAG + heating
                              1. Lu et al., 2004

                                 Annotations:

                                 •    o   examined whether withdrawal reflexes evoked by fast and slow rates of skin heating were differentially modulated by PAG activation. C-fiber mediated withdrawals were found to be inhibited, and A-fiber evoked reflexes unaffected   
                              2. Leith et al, 2007

                                 Annotations:

                                 • following inhibition of COX in PAG>> suppression of C-mediated reflexes, and no effect on A-fibre mediated reflexes
                                 •    Becuase C-ve neurons provide strong facilitation>> The explanation may be that reflexes evoked by A-heat nociceptors are presumably mediated by both C+ve and C−ve neurons. Since the former would have been inhibited and the latter facilitated by PAG stimulation, the net effect on the withdrawal reflex would be null.   
         3. Early studies

            Annotations:

            • inhibitory influences from sites in the midbrain periaqueductal gray (PAG) and from the midline nucleus raphe magnus and adjacent reticular regions in the pons and medulla, the rostral ventromedial medulla (RVM) 
            1. Selectivity of descending control
               1. selective- Mayer et al (1971)

                  Annotations:

                  •   Behavioural responses o  Following stimulation of PAG>> highly selective for behaviours evoked by noxious stimuli (animals didn’t respond to noxious stimuli, but responded to non-noxious stimuli)   
               2. non-selective Bennett and Mayer (1979)

                  Annotations:

                  •   Electrophysiological o   Stimulation of PAD>> non-selective inhibition of both nociceptive/ non-nociceptive responses of DH neurons o   Explanation- non-selective effects possibly due to activation of other fibres that modulate the activity of the PAG   
               3. actual/ potential damage signaled by

                  Annotations:

                  • Information about actual or potential tissue damage in the periphery is conveyed to the spinal dorsal horn in A- and C-fiber nociceptors- and they both have different electrophysiological properties, signal different qualities of acute pain and have distinct roles in the development and maintenance of chronic pain 
                  1. A-noci
                  2. C-noci
         4. (-) Chemical vs electrical stimulation
            1. Waters and Lumb, 1997

               Annotations:

               • Waters and Lumb, 1997- stimulation by electrical or chemical means, at the same site of PAG>> led to non-selective and selective effects respectively   
      2. Behavioral responses
         1. withdrawal response
      3. Drugs
         1. Opiods
         2. Cannabanoids
         3. NSAID
         4. COX-inhibition
            1. Leith et al., 2007

               Annotations:

               • COX inhibition- see PAG + heating experiments
         5. PEG2
            1. hyoeralgesia

               Annotations:

               • Prostaglandin E2 (PGE2) in the medial preoptic area similarly activates ON-cells and produces hyperalgesia (Heinricher et al., 2004). 
      4. Diabetes hyperalgesia

         Annotations:

         • Mohammadi-Farani et al (2010)

         Attachments:

         • Descending control of pain
   4. Inputs
      1. Amy

         Annotations:

         • amygdala
      2. ACC

         Annotations:

         • anterior cingulate cortex
      3. DMH

         Annotations:

         • dorsomedial nucleus of the hypothalamus 
      4. MPC

         Annotations:

         • medial prefrontal cortex
3. faciliatory/ inhibitory

   Annotations:

   • has both facilitatory and inhibitory descending control

1. facitilatory
   1. dynamic balance

      Annotations:

      • facilitatory and inhibitory influences on spinal events are often reported to originate from a single brain region (e.g., Zhuo and Gebhart, 1997)
   2. increase facilitation

      Annotations:

      • descending facilitation of spinal nociception is a major contributor to central sensitization and the development of secondary hyperalgesia, indicating that the balance shifts in favor of facilitation in the transition from acute to chronic pain
2. inhibitory
3. Stress/ threats

   Annotations:

   •    ·         >> descending control might be involved in response to stressful/ threatening stimuli- Selective suppression of nociception would allow an organism to respond in an appropriate manner to a life-threatening situation without the distraction or counterproductive motor responses that might be evoked by noxious input   

1. DRt

   Annotations:

   • dorsal reticular nucleus
   1. facilitatory?

      Annotations:

      • mainly, but may also be inhibitory
      1. Lima and Almeida, 2002

         Annotations:

         • experimental stimulation of the DRt facilitates behavioral measures of nociception, implicating this region in a positive feedback loop that is closely tied to processing of nociceptive information 
2. VLM

   Annotations:

   • ventrolateral medulla 
   1. inhibitory?

      Annotations:

      • reciprocal connections of the DRt and VLM with the spinal cord provide an important anatomical background for the participation of those areas in central sensitization during chronic pain
      1. stimulation- inhibitory
      2. lesions- disinhibition
      3. ON-OFF cells?

         Annotations:

         •    VLM may, like the RVM, exert a facilitatory influence, as neurons with features of ON and OFF cells have been identified in this region (Pinto-Ribeiro et al., 2006).   
   2. Reciprocal connections with spinal cord

      Annotations:

      • reciprocal connections of the DRt and VLM with the spinal cord provide an important anatomical background for the participation of those areas in central sensitization during chronic pain
   3. chronic inflammation
      1. c-fos studies

         Annotations:

         • Pinto et al (2007)-  Acute inflammation induced by intra-articular injection of a solution of PGE2 and bradykinin induces a strong neuronal activation both at the VLM and the spinal cord. This suggests that at the initial phases of inflammation, descending inhibition from the VLM fails to inhibit the strong nociceptive transmission arising from the spinal cord 
         • Pinto et al 2006; 2007- With chronic inflammation, innocuous stimulation of the affected paw gives rise to an inverse correlation between c-fos expression in the VLM and dorsal horn, suggesting that descending inhibition is sufficient to suppress spinal activation. However, when intense pinch is applied to the same limb, strong c-fos expression is seen at both levels, implying either that the c-fos expression represents activated pain-facilitating neurons or, if expression is in pain-inhibiting neurons, that descending inhibition is insufficient to suppress activation of the dorsal horn neurons 
         1. Pinto et al