Mediation of Movement-Induced Breakthrough Cancer Pain by IB4-Binding Nociceptors in Rats

Abstract

Cancer-induced bone pain is characterized by moderate to severe ongoing pain that commonly requires the use of opiates. Even when ongoing pain is well controlled, patients can suffer breakthrough pain (BTP), episodic severe pain that "breaks through" the medication. We developed a novel model of cancer-induced BTP using female rats with mammary adenocarcinoma cells sealed within the tibia. We demonstrated previously that rats with bone cancer learn to prefer a context paired with saphenous nerve block to elicit pain relief (i.e., conditioned place preference, CPP), revealing the presence of ongoing pain. Treatment with systemic morphine abolished CPP to saphenous nerve block, demonstrating control of ongoing pain. Here, we show that pairing BTP induced by experimenter-induced movement of the tumor-bearing hindlimb with a context produces conditioned place avoidance (CPA) in rats treated with morphine to control ongoing pain, consistent with clinical observation of BTP. Preventing movement-induced afferent input by saphenous nerve block before, but not after, hindlimb movement blocked movement-induced BTP. Ablation of isolectin B4 (IB4)-binding, but not TRPV1 ϩ , sensory afferents eliminated movement-induced BTP, suggesting that input from IB4-binding fibers mediates BTP. Identification of potential molecular targets specific to this population of fibers may allow for the development of peripherally restricted analgesics that control BTP and improve quality of life in patients with skeletal metastases.

Pros and Cons of Clinically Relevant Methods to Assess Pain in Rodents

“…Treatments that alleviate pain induce CPP across a range of pain conditions such as incision, inflammation, post-operative pain, nerve injury, osteoarthritis, cancer pain, spinal cord injury, and cephalic pain (Davoody et al, 2011;De Felice et al, 2010Havelin et al, 2017;Hung et al, 2015;King et al, 2011;Liu et al, 2011;Okun et al, 2011, 2012, Park et al, 2016, 2013Remeniuk et al, 2015;Sufka, 1994;Xie et al, 2014;Yang et al, 2014). Drugs that are not rewarding in the absence of pain become rewarding in the presence of chronic pain.…”

“…Treatments that do not directly activate the reward pathway produce CPP in animals with chronic pain. For example, peripheral nerve block, administration of spinal ωconotoxin or clonidine, and RVM lidocaine induce CPP in animals in pain but not in control animals (Havelin et al,2017;King et al, 2009, 2012Remeniuk et al, 2015). Relief from the aversive component of chronic pain motivates the animal to increase time in the treatment-paired chamber.…”

“…spinal clonidine, ω-conotoxin, systemic gabapentin, duloxetine), but not drugs that fail to alleviate spontaneous pain (King et al, 2009). The focus on spontaneous/ongoing pain allows for exploration of mechanistic differences between spontaneous and evoked pain states (Havelin et al, 2017;King et al, 2011;Okun et al, 2011;Remeniuk et al, 2015). Another advantage of CPP is that because assessment of the analgesic effects of treatment occurs 24 hours after the last drug treatment, CPP is not confounded by undesirable side effects such as sedation or inhibition of movement.…”

Regulatory role of capsaicin-sensitive peptidergic sensory nerves in the proteoglycan-induced autoimmune arthritis model of the mouse

“…Concerning a direct effect on the pain component, it has to be pointed out that the involvement of capsaicin-sensitive primary afferents in mechanonociception, mechanical hyperalgesia, and allodynia in models of inflammatory, neuropathic, or cancer pain had been extensively investigated. Several studies could not confirm a role for this subpopulation of sensory neurons in mechanical hyperalgesia in contrast with thermal hyperalgesia and spontaneous pain in these conditions [ 44 – 49 ], which might be due to major differences in peripheral and central sensitization mechanisms in these chronic pathophysiological processes. However, in our long-lasting arthritis model with mixed inflammatory, neuropathic, and degenerative mechanisms, we found a markedly diminished mechanical hyperalgesia in desensitized arthritic animals, which points to the feasibility of targeting TRPV1 channels and TRPV1-expression sensory nerves for analgesia at the periphery.…”

Mechanisms Underlying Bone and Joint Pain

“…Recent RNA sequencing data indicate that multiple classes of nociceptors exist [13]. Distinct RNA transcription profiles and protein expression in conjunction with behavioral experiments demonstrate specific nociceptive responses from nociceptor populations that have distinct molecular characteristics [13–17, 11, 18, 19]. Studies such as these demonstrate that different fiber populations convey distinct sensory information depending on modality (thermal, chemical, mechanical) as well as areas of innervation (cutaneous vs deep tissue) as outlined in the labeled line hypothesis of sensory processing [15–17, 11, 18, 19].…”