Transgenic mice possessing increased numbers of nociceptors do not exhibit increased behavioral sensitivity in models of inflammatory and neuropathic pain

Abstract

At least two classes of neciceptors can be distinguished based on their growth factor requirements: glial cell-line derived neurotrophic factor (GDNF)- and nerve growth factor (NGF)-dependent primary afferent neurons. Based on numerous anatomical and biochemical differences, GDNF- and NGF-dependent neurons have been proposed to be involved in the development of different types of persistent pain. To examine this hypothesis we used two lines of transgenic mice that contained a supernormal number of either NGF- or GDNF-dependent neurons (referred to as NGF-OE and GDNF-OE mice, respectively). These mice were tested in a model of inflammatory pain (induced by injection of complete Freund's adjuvant) and neuropathic pain (using a spinal nerve ligation protocol). Contrary to expectations, neither line of transgenic mice became more hyperalgesic following induction of persistent pain. In fact, NGF-OE mice recovered more rapidly and became hypoalgesic despite extensive paw swelling in the inflammatory pain model. In the neuropathic pain model, only wildtype mice became hyperalgesic. Real-time PCR analysis showed that the NGF-OE and GDNF-OE mice exhibited changes in neuronal-specific mRNAs in the dorsal root ganglia but not the spinal cord dorsal horn. These results indicate that increasing the number of nociceptors results in potent compensatory mechanisms that may begin with changes in the sensory neurons themselves.

Glial Cell Line-Derived Neurotrophic Factor Family Members Sensitize NociceptorsIn Vitroand Produce Thermal HyperalgesiaIn Vivo

“…These data support a functional model in which most TRPV1-positive cells express both TrkA and GFR␣3, whereas a less numerous group of cells express TRPV1, GFR␣1, and/or GFR␣2. In mice, GFR␣3 is expressed primarily in TrkA-positive afferents (Zwick et al, 2003). Artemin is most dramatically upregulated (10-fold) at day 1 after CFA injection; this immediately precedes the time period of greatest thermal hyperalgesia in CFA-induced inflammation (1-4 d).…”

“…Detailed methods for this procedure have been reported previously (Zwick et al, 2003). Briefly, 20 mice were anesthetized with isoflurane, and 20 l of complete Freund's adjuvant (CFA) emulsion was injected into the plantar surface of both hindpaws.…”

“…Therefore, we examined the expression levels of NGF, artemin, neurturin, and GDNF mRNA in footpad skin during CFA-induced inflammation. CFA injection causes thermal hyperalgesia with a consistent time course that begins within 1 d and lasts for 7-10 d (Fairbanks et al, 2000;Zwick et al, 2003). Expression data are shown in Table 3 and Figure 8 A: mRNA for all four growth factors is dynamically regulated during inflammation.…”

Artemin Overexpression in Skin Enhances Expression of TRPV1 and TRPA1 in Cutaneous Sensory Neurons and Leads to Behavioral Sensitivity to Heat and Cold

“…In addition, unlike ART-OE animals, NGF-OE mice and mice that overexpress GDNF in skin (GDNF-OE) mice showed no increase in TRPV1 mRNA in DRG neurons (Zwick et al, 2003;Molliver et al, 2005).…”

Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

“…NGF produced in the bladder has been suggested to modulate peripheral mechanical nociception in the presence of cystitis (29), and studies involving NGF have implicated its importance in the development of visceral hyperalgesia and inflammatory pain (41,51,53,78). Intravesical administration of NGF decreases the threshold of the hindpaw to mechanical stimulation similar to CYP (28).…”