Neuroendocrinology of Pain

1. Neuroendocrinology of Pain Mary Holder mhold001@umaryland.edu

2. What is Pain? • Pain is sensation of discomfort, distress, or agony, resulting from the stimulation of specialized nerve endings. It serves as a protective mechanism. • Sensations of pain are often felt as pricking, burning, aching, stinging, and soreness.

3. Pain is a Subjective State • There is a difference between pain and nociception. • Pain is a subjective feeling, not identical or linearly related to activity in nociceptive systems. • There is no universal painful stimulus • Pain is a product of the brain’s abstraction and elaboration of sensory input; it is perception mediated by neural mechanisms of nociception.

4. Nociception • Nociception is a submodality of somatic sensation like touch, pressure, and position; it is the activity in the peripheral sensory pathways that respond to tissue damaging stimuli • Nociceptors are sensory receptors that are activated by noxious insults to peripheral tissue. • Nociceptors are often free nerve endings.

5. Nociceptors • Thermal • Extreme heat or cold, Aδ fibers • Mechanical • Intensive pressure, Aδ fibers • Polymodal • High intensity mechanical, chemical, or thermal stimuli, C fibers Different pain sensations come from the same stimuli. Early fast sharp pain from the thermal and mechanical Aδ fibers. Later prolonged aching/burning from the polymodal C fibers.

6. Types of Pain • Peripheral Pain • Direct activation of nociceptors in response to damaging noxious stimuli • Inflammatory Pain • Damaged Tissue, inflammatory and tumor cells release chemical mediators that activate or modulate nociceptive afferents • Neuropathic Pain • Direct injury or dysfunction of the nerves

7. Dorsal Horn • Fibers terminate in dorsal horn of spinal cord. • Chemical transmitter mediated • Glutamate • Major excitatory transmitter released by Aδ and C fibers. • Substance P • Elicit slower excitatory potentials

8. Spinothalamic Tract • Project to Contralateral spinal cord • Ascend in anterolateral white matter • Terminates in thalamus • Higher Brain Areas • Somatosensory Cortex • Cingulate Cortex • Insular Cortex

9. Descending Inhibitory System • Tonically Active • Major source of input is NRM • Stimulation of NRM produces analgesia • PAG is a primary projection to NRM • Stimulation of PAG also produces analgesia • Stimulation activates descending pathways to inhibit nociception.

10. Endogenous Pain Control • Opioid Peptides: enkephalins,β-endorphins, dynorphins • Opioid Receptors: µ, δ, κ • Inhibit nociceptive firing in dorsal horn • Postsynaptic inhibition by increasing K+ conductance • Presynaptic inhibition by inhibiting release of glutamate and substance P • Morphine acts in this way; the effects can be blocked by naloxone at PAG or NRM

11. Sex Prevalence of Various Disorders Berkley 1997

12. Sex Differences in Pain in Humans • Galton (1894): women more sensitive than men in two point discrimination task • Herren (1933): women have lower pain thresholds in the premenstrual phase (5 day prior to menses) • Weinstein & Sersen (1961): women more sensitive on sole of foot and palm of hand • Procacci et al. (1970): lower pain threshold in women than men; pain threshold increases in both sex with increasing age.

13. Robinson & Short (1977): nipple and breast sensitivity increase postpubertally in women but not men. • Larkin et al. (1986): Women more sensitive than men to electrocutaneous stimulation. In short, women show lower thresholds, higher ratings, and less tolerance to pain.

14. Sex Differences in Pain Mechanisms

15. Methods of Studying Pain in Humans • Self-Reports of Endogenous Pain • Use of a variable pressure algometer to assess pressure pain thresholds • Temperature pain thresholds • Electrocutaneous stimulation thresholds

16. Methods of Studying Pain in Rat • Tail Flick Latency or Tail Withdrawal • Noxious heat applied to the tail • Hot Plate Latency or Thermal Withdrawal • Noxious temperature (50-58°C) • Foot Shock (Jump threshold) • Electrical stimulus applied to the feet, jumps from charged grid • Formalin • Inject 5-10% into hindpaw • Quantify time spend licking • Freund’s Adjuvant (CFA) – chronic inflammatory pain • Inject into paw

17. In the Rat • Levin & Taiwo (1989): β-estradiol decreased pain thresholds 48 hours post-injection • Alosi & Ceccarelli (2000): Estradiol increased formalin-induced paw licking. • Kelly et al. (2002): Estradiol give i.c.v. exacerbate pain-related behavior in male rat.

18. Effect of Sex on Baseline Nociception Barret et al. (2002)

19. Gonadal Steroids (in rat) Stoffel et al. (2003) • In males, hormone replacement does not affect hot plate latency. • In females, giving E2, E2 + P4 and T produces an increase in hot plate latency. In the animal literature, there exist conflicting results as to the effect of gonadal steroid on pain.

20. Menstrual Cycle • Pain threshold highest in follicular. • Pain threshold lowest in luteal phase for most stimuli. • Electrical stimuli have the lowest threshold in follicular phase. • Migraine is associated with high Estrogen and Progesterone levels.

21. Estrous Cycle • Females had a higher threshold for tail pressure and equal hindpaw threshold compared to males. • Females in Estrus and Proestrus were lower than those in Met- and Diestrus. V. Kayser et al (1996)

22. So how can Estrogen be acting to influence mechanisms of pain?

23. Estrogen in the Dorsal Horn • Estrogen could be acting on the DRG neurons. • Estrogen R are in the DRG. • Estrogen R are colocalized with enkephalin expressing neurons; E2 administration increases spinal cord enkephalin mRNA levels in OVX females.

24. Estrogen and Prostaglandin • E2 acts on blood vessel walls to synthesize prostaglandins. • Prostaglandin-E is important in the CNS for central mechanisms of sensitization. • An increase in Prostaglandin results in an increase in pain

25. Conclusion of Gonadal Effects on Pain • Estrogen has been shown to both increase and decrease pain thresholds. • The effect of estrogen levels depend on the nature of the pain assay.

26. Sex Differences in Opioid Analgesia • In rodents, opioids are more potent or efficacious in males; T may enhance opioid potency in the adult male.

27. There is an organizational role of gonadal steroids. • OVX + T given on PN 1 or 2 results in a morphine sensitivity like that of a intact male. • GDX on PN 1 or 2 results in less morphine sensitivity analogous to a normal female.

28. Strategies • Compare analgesia in gonadally intact vs. gonadectomized subjects. • Compare analgesia in gonadectomized subjects with and without hormone replacement. • Compare analgesia at different stages of estrous cycles.

29. Effect of GDX and steroid hormone replacement in males Stoffel et al. (2003)

30. Effects of Estrous Stage on Morphine Antinociception Stoffel et al. (2003)

31. Effects of Steroid Hormone Replacement in Female Rats Stoffel et al. (2003)

32. Sex Differences in the µ Opioid System • Endogenous and µ opioid receptors are implicated in suppression of pain. • Males rats show greater antinociception that females after administration of morphine. • Males also show more activation than females.

33. Parturition • Opioid mediates mediate an increase in pain threshold – activated by sex hormones • Progressive levels of E2 and P4 activate κ-opioid receptors analgesic system. • Both ER and κ-opioid R are located in spinal dorsal horn in the lumbaroscaral area.

34. Sex Differences in δ- & κ- Opioid Systems • Under basal conditions, both systems are quiescent. • Blockade of spinal δ- or κ- opioid R by BNTX or nor-BNI, respectively, blocks antinociception in pregnant animals. • There is no effect of blocking δ- or κ- opioid R in non-pregnant animals.

35. E2 and P4 pregnancy blood levels can active the δ- or κ- opioid system. • Administering pregnancy levels of E2 or P4 alone or of E2 with the delayed addition of P4 failed to increase pain threshold. • Activation of δ- or κ- opioid receptors alone is not sufficient to elevate pain thresholds.

36. PAG Involvement in Opioid Analgesia • PAG is start of descending pathway

37. Sex differences in expression of opioid receptors • PAG contains a lot of opioid receptors • Profound sex differences in µ receptor activation in rat PAG • Females have less activation of µ opioid system

38. Conclusions of Gonadal Effects on Opioid Systems • The µ opioid system is the one that generally modulates pain response. • High levels of both estrogen and progesterone can increase pain thresholds; this is mediated by the other opioid receptors. • Descending inhibition of pain depends upon the opioid receptors and the brain areas of the NRM and PAG.

39. Things to Keep In Mind • The pain literature is huge and often contradictory. • There is no standard way to assess pain – even when using the same assay. • The hormones may not be given at physiological levels – this could help explain the contradictory data. • The hormones differentially affect the different opioid receptors. • The doses of opioid agonists are not standardized.