TY - JOUR
T1 - Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain
AU - De Felice, Milena
AU - Sanoja, Raul
AU - Wang, Ruizhong
AU - Vera-Portocarrero, Louis
AU - Oyarzo, Janice
AU - King, Tamara
AU - Ossipov, Michael H.
AU - Vanderah, Todd W.
AU - Lai, Josephine
AU - Dussor, Gregory O.
AU - Fields, Howard L.
AU - Price, Theodore J.
AU - Porreca, Frank
N1 - Funding Information:
Much evidence suggests that the sensory experience of pain depends on descending pain modulatory circuits arising ultimately from the rostral ventromedial medulla (RVM) [16,17] . Cells in the RVM project to the spinal dorsal horn and either enhance (ie, ON cells) or inhibit (ie, OFF cells) nociceptive traffic [17,19,74] . After experimental nerve injury, facilitatory influences from the RVM can maintain central sensitization and expression of neuropathic pain behaviors [4,54,60,62] . The clinical relevance of descending modulation is supported by the efficacy of drugs used for the treatment of neuropathic pain. Thus, number needed to treat analyses consistently demonstrate that the most effective medications are those that engage descending pain inhibitory circuits or that mimic the consequences of descending inhibition [20] . Such compounds include tricyclic antidepressants [42,46] , serotonin–norepinephrine reuptake inhibitors [36,42] and norepinephrine reuptake blockers such as duloxetine, a compound with U.S. Food and Drug Administration approval for neuropathic pain [21] . Spinal clonidine has been shown to be effective in neuropathic patients [14,43] . Additionally, opiates are efficacious in neuropathic pain [20] and act in part by engagement of descending inhibition [15,17,33] . Finally, recent evidence suggests the possibility that gabapentinoids may also engage descending inhibition from the locus coeruleus [27,28] .
PY - 2011/12
Y1 - 2011/12
N2 - A puzzling observation is why peripheral nerve injury results in chronic pain in some, but not all, patients. We explored potential mechanisms that may prevent the expression of chronic pain. Sprague Dawley (SD) or Holtzman (HZ) rats showed no differences in baseline sensory thresholds or responses to inflammatory stimuli. However, spinal nerve ligation (SNL)-induced tactile allodynia occurred in approximately 85% of SD and 50% of HZ rats, respectively. No apparent differences were observed in a survey of dorsal root ganglion or spinal neuropathic markers after SNL regardless of allodynic phenotype. SNL-induced allodynia was reversed by administration of lidocaine within the rostral ventromedial medulla (RVM), a site that integrates descending pain modulation via pain inhibitory (ie, OFF) and excitatory (ie, ON) cells. However, in SD or HZ rats with SNL but without allodynia, RVM lidocaine precipitated allodynia. Additionally, RVM lidocaine produced conditioned place preference in allodynic SD or HZ rats but conditioned place aversion in nonallodynic HZ rats. Similarly, RVM U69,593 (kappa opioid agonist) or blockade of spinal α 2 adrenergic receptors precipitated allodynia in previously nonallodynic HZ rats with SNL. All rats showed an equivalent first-phase formalin responses. However, HZ rats had reduced second-phase formalin behaviors along with fewer RVM OFF cell pauses and RVM ON cell bursts. Thus, expression of nerve injury-induced pain may ultimately depend on descending modulation. Engagement of descending inhibition protects in the transition from acute to chronic pain. These unexpected findings might provide a mechanistic explanation for medications that engage descending inhibition or mimic its consequences.
AB - A puzzling observation is why peripheral nerve injury results in chronic pain in some, but not all, patients. We explored potential mechanisms that may prevent the expression of chronic pain. Sprague Dawley (SD) or Holtzman (HZ) rats showed no differences in baseline sensory thresholds or responses to inflammatory stimuli. However, spinal nerve ligation (SNL)-induced tactile allodynia occurred in approximately 85% of SD and 50% of HZ rats, respectively. No apparent differences were observed in a survey of dorsal root ganglion or spinal neuropathic markers after SNL regardless of allodynic phenotype. SNL-induced allodynia was reversed by administration of lidocaine within the rostral ventromedial medulla (RVM), a site that integrates descending pain modulation via pain inhibitory (ie, OFF) and excitatory (ie, ON) cells. However, in SD or HZ rats with SNL but without allodynia, RVM lidocaine precipitated allodynia. Additionally, RVM lidocaine produced conditioned place preference in allodynic SD or HZ rats but conditioned place aversion in nonallodynic HZ rats. Similarly, RVM U69,593 (kappa opioid agonist) or blockade of spinal α 2 adrenergic receptors precipitated allodynia in previously nonallodynic HZ rats with SNL. All rats showed an equivalent first-phase formalin responses. However, HZ rats had reduced second-phase formalin behaviors along with fewer RVM OFF cell pauses and RVM ON cell bursts. Thus, expression of nerve injury-induced pain may ultimately depend on descending modulation. Engagement of descending inhibition protects in the transition from acute to chronic pain. These unexpected findings might provide a mechanistic explanation for medications that engage descending inhibition or mimic its consequences.
KW - Any order
KW - Word
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U2 - 10.1016/j.pain.2011.06.008
DO - 10.1016/j.pain.2011.06.008
M3 - Article
C2 - 21745713
AN - SCOPUS:81055157088
SN - 0304-3959
VL - 152
SP - 2701
EP - 2709
JO - Pain
JF - Pain
IS - 12
ER -