Identification of the Visceral Pain Pathway Activated by Noxious Colorectal Distension in Mice

Abstract

In patients with irritable bowel syndrome, visceral pain is evoked more readily following distension of the colorectum. However, the identity of extrinsic afferent nerve pathway that detects and transmits visceral pain from the colorectum to the spinal cord is unclear. In this study, we identified which extrinsic nerve pathway(s) underlies nociception from the colorectum to the spinal cord of rodents. Electromyogram recordings were made from the transverse oblique abdominal muscles in anesthetized wild type (C57BL/6) mice and acute noxious intraluminal distension stimuli (100–120 mmHg) were applied to the terminal 15 mm of colorectum to activate visceromotor responses (VMRs). Lesioning the lumbar colonic nerves in vivo had no detectable effect on the VMRs evoked by colorectal distension. Also, lesions applied to the right or left hypogastric nerves failed to reduce VMRs. However, lesions applied to both left and right branches of the rectal nerves abolished VMRs, regardless of whether the lumbar colonic or hypogastric nerves were severed. Electrical stimulation applied to either the lumbar colonic or hypogastric nerves in vivo, failed to elicit a VMR. In contrast, electrical stimulation (2–5 Hz, 0.4 ms, 60 V) applied to the rectum reliably elicited VMRs, which were abolished by selective lesioning of the rectal nerves. DiI retrograde labeling from the colorectum (injection sites 9–15 mm from the anus, measured in unstretched preparations) labeled sensory neurons primarily in dorsal root ganglia (DRG) of the lumbosacral region of the spinal cord (L6-S1). In contrast, injection of DiI into the mid to proximal colon (injection sites 30–75 mm from the anus, measured in unstretched preparations) labeled sensory neurons in DRG primarily of the lower thoracic level (T6-L2) of the spinal cord. The visceral pain pathway activated by acute noxious distension of the terminal 15 mm of mouse colorectum is transmitted predominantly, if not solely, through rectal/pelvic afferent nerve fibers to the spinal cord. The sensory neurons of this spinal afferent pathway lie primarily in the lumbosacral region of the spinal cord, between L6 and S1.

Extrinsic primary afferent signalling in the gut

“…Lumbosacral afferents primarily mediate the visceromotor response to colorectal distension in normal mice, as severing pelvic pathways abolishes the response, but lesioning splanchnic pathways has little effect. 143 Lumbosacral dorsal rhizotomy abolishes visceromotor reflexes, but inflammation reinstates a thoracolumbar contribution, 144 which indicates that thoracolumbar vascular afferents can contribute to pain symptoms after inflammatory challenge. However, further up the colon, the situation might be quite different.…”

Spinal afferent nerve endings in visceral organs: recent advances

“…B, The major pain pathway to the colon is via the rectal/pelvic afferents (in red), whose cell bodies lie in L5-S2 DRG. This was established when lesions to rectal nerves abolished the visceromotor response to colorectal distension, while lesions to the lumbar colonic nerves had no effect on the VMR responses (12) …”

“…This was determined largely by lesion studies to the vagus nerve which failed to block painful sensations, whereas lesions to the spinal cord abolished all visceral sensation (12), including those of a noxious origin (12). Despite our understanding of the location of the cell bodies of spinal afferent neurons within DRG (12, 33), one major unresolved mystery is the location of the nerve endings of spinal afferents that actually convert noxious stimuli into nerve action potentials, that are ultimately relayed to the CNS (4, 36).…”

“…There is clear evidence in mammals, that most, if not all painful stimuli arising from internal organs are detected by spinal afferent neurons, whose cell bodies lie in DRG (12,38). This was determined largely by lesion studies to the vagus nerve which failed to block painful sensations, whereas lesions to the spinal cord abolished all visceral sensation (12), including those of a noxious origin (12).…”

Expression and distribution of SP and its NK1 receptor in the brain-gut axis in neonatal maternally separated rat model with visceral hypersensitivity

“…2) SP and NK1Rs were here detected in the lumbosacral spinal cord, because the afferent impulses of pain in the thoracolumbar spine segment are unclear. Furthermore, the distal colon and rectum convey afferent stimuli mainly to the lumbosacral spinal cord along the pelvic nerve (Kyloh et al, 2011). 3) Dorsal horn of the spinal cord is a key area of sensitivity modulation.…”